Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH3:22])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[Cl:3][CH2:6][CH:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH3:22])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Cl)ccc1OC(CO)C(=O)C(C)(C)C
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1OC(CCl)C(=O)C(C)(C)C
Yield: 82.5 %

Procedure:
50 g (0.42 mole) of thionyl chloride were slowly added dropwise at room temperature to a solution of 106 g (0.39 mole) of 1-hydroxy-2-(2-methyl-4-chlorophenoxy)-4,4-dimethylpentan-3-one in 400 ml of methylene chloride, while stirring and using reflux cooling, and the mixture was stirred at room temperature overnight. It was then distilled under reduced pressure. 93 g (82% of theory) of 1-chloro-2-(2-methyl-4-chlorophenoxy)-4,4-dimethyl-pentan-3-one of boiling point 113°-117°C/0.2 mm were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH3:24][S:25]([O-:27])=[O:26].[Na+]>CN(C=O)C.C(Cl)Cl.CO>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[CH:7]=[C:2]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:3]=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CS(=O)[O-]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2[N+](=O)[O-])CC1
Temperature: 100 °C

Procedure:
To a solution of cis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (0.100 g, 0.309 mmol) in DMF (0.55 mL) was added sodium methanesulfinate (0.045 g, 0.371 mmol), and the reaction mixture was heated at 100° C. for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by flash chromatography, eluting with 0-70% 9:1 DCM/MeOH to cis-N-isopropyl-4-(5-(methylsulfonyl)-2-nitrophenylamino)cyclohexanecarboxamide as a bright orange solid (0.124 g, 105% yield). MS (ESI pos. ion) m/z: 384.0 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1>C(O)(=O)C>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:14][CH:4]=[C:3]2[CH:2]([CH3:6])[CH3:1]
Reactant: NNc1ccc(Br)cc1
Reactant: CC(C)CC=O
Solvent: CC(=O)O
Product: CC(C)c1c[nH]c2ccc(Br)cc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
3-Methylbutanal (0.921 g, 10.69 mmol) was added to a solution of (4-bromophenyl)hydrazine (2 g, 10.69 mmol) in acetic acid (100 mL) at 80° C., and the mixture was stirred for 3 h at 120° C. The reaction mixture was concentrated to get the residue, and the residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with saturated bicarbonate solution and brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 2% ethyl acetate in pet ether to afford title compound (1.1 g, 38.4%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.91 (bs, 1H), 7.76 (m, 1H), 7.25-7.20 (m, 2H), 6.95 (d, J=2.4 Hz, 1H), 3.18-3.11 (m, 1H), 1.35 (d, J=6.8 Hz, 6H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33]([O:40][C@@H:41]3[O:49][C@H:48]([CH2:50][OH:51])[C@@H:46]([OH:47])[C@H:44]([OH:45])[C@H:42]3[OH:43])=[N:34][NH:35][C:36]=2[CH:37]([CH3:39])[CH3:38])=[C:27]([CH3:52])[CH:26]=1)[C:17](=[O:19])[NH2:18])=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33]([O:40][C@@H:41]3[O:49][C@H:48]([CH2:50][OH:51])[C@@H:46]([OH:47])[C@H:44]([OH:45])[C@H:42]3[OH:43])=[N:34][NH:35][C:36]=2[CH:37]([CH3:39])[CH3:38])=[C:27]([CH3:52])[CH:26]=1)[C:17](=[O:19])[NH2:18]
Reactant: Cc1cc(OCCCN[C@@H](CCCCNC(=O)OCc2ccccc2)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(OCCCN[C@@H](CCCCN)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 4-[(4-{3-[(S)-5-benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.17 g) in methanol (4 mL) was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.13 g).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][NH2:21])[C:15]=1[I:22].C(#N)C.O.C(O)(C(F)(F)F)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]2[C:5](=[O:11])[NH:21][N:20]=[C:16]2[C:15]=1[I:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1nccc(Br)c1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(I)c(Br)ccn12
Temperature: 20 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of triphosgene (91.7 g, 309 mmol) in THF (800 mL) was added 4-bromo-2-hydrazinyl-3-iodopyridine (32.3 g, 103 mmol) in several portions over 1 h at 20° C. The resulting reaction mixture was stirred for an additional 2 h at 20° C. The reaction was monitored by HPLC (acetonitrile-water-TFA) and completed in 2 h. The reaction mixture was cooled in ice bath and quenched by careful addition of H2O (800 mL). A large amount of solid was precipitated. This was filtered and successively washed with H2O (2×100 mL) and Et2O (100 mL). The filtrate was concentrated in vacuo to reduce volume by 50%. Newly formed solid was then filtered. This 2nd crop was also washed with H2O and Et2O. The two crops were combined and dried under high vacuum to obtain the title compound as a light beige solid (34 g, 100 mmol). MS: [M+H]+=337.9. 1H NMR (400 MHz, DMSO) δ 6.76 (d, J=7.03 Hz, 1H), 7.78 (d, J=7.47 Hz, 1H), 12.68 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([O:62][Si](C(C)(C)C)(C)C)[CH:58]=4)[CH:53]=3)[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([OH:62])[CH:58]=4)[CH:53]=3)[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc5cc(O)ccc5c4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 56.2 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6"'-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.6 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then 1.75 h at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone) affording 20.8 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6"'-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:22]=2)=[N:7][C:6]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1C
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-trifluoromethyl-phenyl boronic acid to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester; ii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester has been saponified to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid; iii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless solid. MS: 432.3 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.2 %

Procedure:
Indole-5-carboxylic acid (3.10 g) was dissolved in tetrahydrofuran (50 ml), and lithium aluminium hydride (1.50 g) was added thereto, followed by heating under reflux for 20 hours. The reaction solution was cooled to room temperature, and ethyl acetate and then a 2N aqueous solution of sodium hydroxide were added thereto to cease the reaction. The reaction solution was dried over anhydrous sodium sulfate and insoluble matters were filtered off. Manganese dioxide (30.00 g) was added to the filtrate, followed by stirring at room temperature for 96 hours. Insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give indole-5-carbaldehyde (1.43 g).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([CH:76]=O)=[CH:74][CH:73]=2)[CH:71]=[CH:70][CH:69]=[N:68]1>C(O)C.CN(C=O)C>[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([C:76]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:74][CH:73]=2)[CH:71]=[CH:70][CH:69]=[N:68]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(-n4cccn4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 38 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-pyrazol-1-yl)benzaldehyde (1.1 eq, 0.056 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 38%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.63 (s, 2H, CH2), 3.70 (s, br, 4H, piperazine N(CH2)2), 6.61 (t, br, J=2.0 Hz, 1H, pyrazole H-4), 7.41 (s, br, 1H, pyridine H-5), 7.80 (s, br, 1H, pyridine H-4), 7.81 (d, J=1.9 Hz, 1H, pyrazole H-3 or H-5), 8.03 (d, J=8.4 Hz, 2H, phenyl H-2 & H-6), 8.26 (s, br, 1H, imidazo[4,5-b]pyridine H-5), 8.30 (d, J=8.5 Hz, 2H, phenyl H-3 & H-5), 8.50 (s, br, 1H, pyridine H-6), 8.58 (s, br, 1H, pyridine H-2), 8.61 (d, J=2.4 Hz, 1H, pyrazole H-3 or H-5), 13.56 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: C(O)(=O)CCCCCCCCCCCCCCCCCCCCC.[NH2:25]CCNCCNCCN.O.C(N)(=O)CCCCCCCCCCCCCCCCCCCCC.NCCNCCNCCN.[F:70][C:71]1[C:72]([O:84][C:85]([F:113])=[C:86]([F:112])[C:87]([F:111])([F:110])[C:88]([F:109])([F:108])[C:89]([F:107])([F:106])[C:90]([F:105])([F:104])[C:91]([F:103])([F:102])[C:92]([F:101])([F:100])[C:93]([F:99])([F:98])[C:94]([F:97])([F:96])[F:95])=[C:73]([S:80](Cl)(=[O:82])=[O:81])[C:74]([F:79])=[C:75]([F:78])[C:76]=1[F:77].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)=C(Cl)Cl>[F:70][C:71]1[C:72]([O:84][C:85]([F:113])=[C:86]([F:112])[C:87]([F:111])([F:110])[C:88]([F:109])([F:108])[C:89]([F:107])([F:106])[C:90]([F:105])([F:104])[C:91]([F:103])([F:102])[C:92]([F:101])([F:100])[C:93]([F:99])([F:98])[C:94]([F:97])([F:96])[F:95])=[C:73]([S:80]([NH2:25])(=[O:82])=[O:81])[C:74]([F:79])=[C:75]([F:78])[C:76]=1[F:77]
Reactant: NCCNCCNCCN
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1OC(F)=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCCCC(N)=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClC(Cl)=C(Cl)Cl
Product: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1OC(F)=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h

Procedure:
Behenic acid (98.4 g., 0.3 mol) and triethylenetetramine (43.8 g, 0.3 mol) was reacted at 158°-161° C. until 0.3 mol of water had been evolved (25 minutes) 47.4 g (0.1 mole) of the resulting triethylenetetramine monobehenamide was dissolved in 50 ml. of perchloroethylene. To the resulting solution was added a mixture of 80.0 g (0.12 mol) of perfluorodecenyloxybenzenesulfonyl chloride and 7.0 g of sodium carbonate over a 20 minute period, while holding the temperature at 95°-120° C. After one hour at 90°-120° C., the mixture was worked up as in the preceding example to yield the product, 1.2 perfluorodecenyloxybenzenesulfonamide of triethylene tetramine monobehenamide, a tan, hard, waxy, solid with good oil, water and soil repellancy.
Reaction SMILES: [C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[NH:9][C:10]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:27]>C(OCC)(=O)C.O1CCOCC1>[ClH:27].[C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[NH:9][C:10]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cn(C(C)(C)C)nc1C(=O)N2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2′-tert-butyl-7′-oxo-2′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (70 mg, 0.19 mmol) in ethyl acetate (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (2 mL) and the mixture was stirred 3 hours at room temperature. The volatiles were removed under reduced pressure and the resultant colorless solid was triturated from heptanes (10 mL) and dried under reduced pressure to yield 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (56 mg) as an off-white solid. +ESI (M+H) 263.1; 1H NMR (500 MHz, DMSO-d6, δ): 8.72 (m, 2H), 7.92 (s, 1H), 7.75 (s, 1H), 3.20 (br. s, 2H), 3.09 (br. s., 2H), 2.78 (s, 2H), 1.79 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O.[CH:27]([CH:30]1[NH:35][CH2:34][CH2:33][NH:32][C:31]1=[O:36])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH2:20]([N:8]1[CH2:9][CH2:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C@@H:7]1[CH2:6][N:35]1[CH2:34][CH2:33][NH:32][C:31](=[O:36])[CH:30]1[CH:27]([CH3:29])[CH3:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)C1NCCNC1=O
Reactant: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
((2R)-1,4-dibenzyl-2-piperazinyl)methyl methanesulfonate (0.450 g, 1.202 mmol) was combined with 3-isopropylpiperazin-2-one (0.179 g, 1.262 mmol, ChemBridge, San Diego, Calif.) and potassium carbonate (0.498 g, 3.60 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (5.46 mL) and heated at 130° C. After 1 h, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration, the crude residue was purified by silica gel chromatography (2.5-8.5% MeOH in CH2Cl2) to give 4-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone (212 mg).
Reaction SMILES: [C:1]([NH:9][N:10]=[C:11](OCC)[CH2:12][CH2:13][CH2:14][CH3:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]1[CH:38]=[CH:37][C:24]([O:25][CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH2:39][CH2:40][CH3:41])[CH:22]=1.C(Cl)(Cl)Cl>C(O)C>[CH2:12]([C:11]1[N:19]([CH2:20][C:21]2[CH:38]=[CH:37][C:24]([O:25][CH:26]([C:27]([O:29][CH3:30])=[O:28])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([CH2:39][CH2:40][CH3:41])[CH:22]=2)[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(=NNC(=O)c1ccccc1)OCC
Reactant: CCCc1cc(CN)ccc1OC(C(=O)OC)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCc1nnc(-c2ccccc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(CCC)c1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 36.7 %

Procedure:
To a solution of 43.2 mg (0.175 mmol) of ethyl valerate benzoylhydrazone (from Step K) in 0.2 ml of ethanol was added a solution of 82 mg (0.262 mmol) of methyl 2-(4-aminomethyl-2-propylphenoxy)-2-phenylacetate (from Step J) in 0.2 ml of ethanol. The resulting solution was stirred under N2 at 50° C. for 5.5 hours. After dilution with 0.4 ml of ethanol, the solution was then stirred at 70° C. under a condenser for 13 hours. Next, the solution was co-evaporated with CHCl3. The residue was chromatographed twice in silica gel columns (gradient elution, first with 0.5-3% and then with 0.3-2% MeOH in CHCl2) to give 32 mg (37%) of the title compound as a white glass; homogeneous by TLC in 9:1 CH2Cl2 -MeOH.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: Cc1ccc(Br)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(C)nc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-methylpyridine.
Reaction SMILES: [C:1]1([OH:14])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:10]([O:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:1](=[O:14])[CH3:2])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1)(=[O:13])[CH3:9]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Temperature: -15 °C
Yield: 185.6 %

Procedure:
An amount of 4,4'-biphenol (200 g, 1.07 moles), (Aldrich Chemical Company, Milwaukee, Wis.), and 1000 ml of acetic anhydride were added to a 2-liter boiling flask equipped with a cold water condenser and a polytetrafluoroethylene-coated magnetic stirring bar. The mixture was heated to reflux under nitrogen and all of the solid dissolved. The solution was refluxed for 20 hours, then cooled in a freezer at -15° C. overnight. The white crystals that were formed were isolated by filtration, washed with cold acetic anhydride and dried in a 100° C. vacuum oven overnight yielding 268.4 g of 4,4'-diacetoxybiphenyl with a m.p. of 162.7° C. to 164.0° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CBr
Reactant: OCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1cccs1
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To a stirring 25 mL solution of 1.14 g (10 mmol) of thiophenemethanol in THF was added 0.24 g (10 mmol) of NaH. After the evolution of gas had ceased, 1.53 g (10 mmol) of methyl bromoacetate was added to the reaction. After 15 minutes, the reaction mixture was filtered. The solvent was removed under reduced pressure. The residue was then dissolved in 50 mL of EtOAc. The organic layer was washed with 3×50 mL of H2O, and was treated in the manner described above in Example 7. The residue was chromatographed to yield 0.91 g (49%) of product. Analysis calculated for C8H10O3S (M.W. 186.23): C, 51.60; H, 5.41. Found: C, 51.41; H, 5.60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.Cl.C[O:46][C:47](=[O:65])[C@@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[C:58]([CH2:62][F:63])[CH:57]=2)=[CH:52][CH:51]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:64][C@@H:48]([CH2:49][C:50]5[CH:55]=[CH:54][C:53]([C:56]6[CH:61]=[CH:60][N:59]=[C:58]([CH2:62][F:63])[CH:57]=6)=[CH:52][CH:51]=5)[C:47]([OH:46])=[O:65])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(CF)c2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(CF)c2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid and (S)-2-amino-3-[4-(2-fluoromethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 861.