Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH3:13])[CH2:5][CH2:6][CH:7]([O:11][CH3:12])[CH:8]([CH3:10])[CH3:9].ClC(Cl)(Cl)C(O)=O.[OH-].[Na+].[BH4-].[Na+]>CO.O.O1CCCC1>[OH:2][CH2:3][CH:4]([CH3:13])[CH2:5][CH2:6][CH:7]([O:11][CH3:12])[CH:8]([CH3:9])[CH3:10]
Reactant: COC(CCC(C)C(OC)OC)C(C)C
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(CCC(C)CO)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10.9 g. of 1,1,5-trimethoxy-2,6-dimethylheptane in 200 ml. of tetrahydrofuran and 60 ml. of water is treated with 1 g. of trichloroacetic acid and then the mixture heated at 60° for 1 hour. After cooling, there is added 40 ml. of 2N sodium hydroxide in methanol followed by 2 g. of powdered sodium borohydride. The reaction mixture is stirred at room temperature for 3 hours and then concentrated and extracted with ether. The ethereal extracts are evaporated under reduced pressure to give crude 1-hydroxy-5-methoxy-2,6-dimethylheptane which can be purified by distillation.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@H:21]([OH:22])[C@H:20]([CH3:23])[CH:19]=[C:18]([CH3:24])[CH:17]=[C:16]([O:25][CH3:26])[C:14](=[O:15])[O:13][C@H:12]([C@H:27]([C@@H:29]([OH:56])[C@@H:30]([C@:32]2([OH:55])[O:37][C@H:36](/[CH:38]=[CH:39]/[CH3:40])[C@@H:35]([CH3:41])[C@H:34]([O:42][C@@H:43]3[O:48][C@H:47]([CH3:49])[C@@H:46]([O:50][C:51]([NH2:53])=[O:52])[C@H:45]([OH:54])[CH2:44]3)[CH2:33]2)[CH3:31])[CH3:28])[C@@H:11]([O:57][CH3:58])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:59])[CH2:6][C@@H:5]([CH3:60])[C@@H:4]1[OH:61].P([O-])([O-])([O-])=O.[CH3:67]O>>[CH3:1][CH2:2][C@@H:3]1[C@H:21]([OH:22])[C@H:20]([CH3:23])[CH:19]=[C:18]([CH3:24])[CH:17]=[C:16]([O:25][CH3:26])[C:14](=[O:15])[O:13][C@H:12]([C@H:27]([C@@H:29]([OH:56])[C@@H:30]([C@:32]2([O:55][CH3:67])[O:37][C@H:36](/[CH:38]=[CH:39]/[CH3:40])[C@@H:35]([CH3:41])[C@H:34]([O:42][C@@H:43]3[O:48][C@H:47]([CH3:49])[C@@H:46]([O:50][C:51]([NH2:53])=[O:52])[C@H:45]([OH:54])[CH2:44]3)[CH2:33]2)[CH3:31])[CH3:28])[C@@H:11]([O:57][CH3:58])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:59])[CH2:6][C@@H:5]([CH3:60])[C@@H:4]1[OH:61]
Reactant: C/C=C/[C@H]1O[C@@](O)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Reactant: CO
Agent: C/C=C/[C@H]1O[C@@](O)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Product: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a thoroughly heated 50 ml flask, 800 mg (0.92 mmol) of concanamycin A are dissolved in 19 ml of dry MeOH. 15 mg of FeCl3 (0.09 mmol, 0.1 equiv.) in 1 ml of MeOH are then added and the mixture is stirred for 15 min at room temperature. After the addition of 20 ml of phosphate buffer (pH=7, Merck), the solution is transferred to a 250 ml flask and the organic solvent is carefully removed in vacuo. The remaining aqueous residue is extracted with CHCl3 and, after customary working-up, is filtered on silica gel (system D, 4×10) to yield the title compound. M.p. 141° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:17]#[N:18])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)C.Cl.[NH2:20][C:21]([NH2:23])=[NH:22].C(=O)([O-])[O-].[K+].[K+].NN1C=C(CCCC2C=CC(OC)=CC=2)C(N)=NC1>CN(C)C=O>[NH2:22][C:21]1[N:23]=[C:17]([NH2:18])[C:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:4][N:20]=1
Reactant: CCOC=C(C#N)CCCc1ccc(OC)cc1
Reactant: N=C(N)N
Agent: COc1ccc(CCCC2=CN(N)CN=C2N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(CCCc2cnc(N)nc2N)cc1

Procedure:
This compound was prepared in a manner analogous to that of Example 2, Step E, using 0.8 gram (0.003 mole) of 1-ethoxy-2-cyano-5-(4-methoxyphenyl)-1-pentene, 1.3 grams (0.012 mole) of guanidine hydrochloride, and 2.7 grams (0.018 mole) of potassium carbonate in 15 mL of N,N-dimethylformamide. The yield of 1,4-diamino-5-[3-(4-methoxyphenyl)propyl]pyrimidine was 0.5 gram, mp 151°-154° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38](N4CCN(C)CC4)[CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:49][N:50]([CH3:67])[CH2:51][CH2:52][O:53][C:54]1[CH:55]=[N:56][C:57](C2C=CC(O)=CC=2)=[N:58][CH:59]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:37]=[CH:38][C:39]([C:57]4[N:56]=[CH:55][C:54]([O:53][CH2:52][CH2:51][N:50]([CH3:67])[CH3:49])=[CH:59][N:58]=4)=[CH:40][CH:41]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CN(C)CCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CN1CCN(c2cccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)CC1
Product: CN(C)CCOc1cnc(-c2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)nc1

Procedure:
The title compound 112D was prepared in a similar manner to the synthesis of compound 105 by substituting compound 87A with compound 112C: 1H NMR (DMSO-d6): δ 12.84 (s, 1H), 9.70 (s, 1H), 8.64 (s, 2H), 8.23 (d, J=8.85 Hz, 2H), 8.04 (d, J=7.93 Hz, 1H), 7.79 (d, J=8.24 Hz, 1H), 7.57-7.61 (m, 2H), 7.34-7.49 (m, 4H), 7.02 (t, J=8.85 Hz, 2H), 6.97 (d, J=8.85 Hz, 1H), 4.93 (s, 2H), 4.52-4.54 (m, 2H), 4.01 (t, J=6.41 Hz, 2H), 3.87 (t, J=5.95 Hz, 2H), 2.95 (t, J=5.8 Hz, 2H), 2.82-2.85 (m, 2H), 1.95-2.00 (m, 2H): ESI (+)/MS: 730 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.O.[NH2:12][NH2:13]>C(O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:12][NH2:13])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: COc1ncc(Br)nc1Br
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ncc(Br)nc1NN
Temperature: 80 °C

Procedure:
A 100 mL round bottom flask was charged with 3,5-dibromo-2-methoxypyrazine (0.50 g, 1.9 mmol), hydrazine hydrate (0.47 g, 9.4 mmol) and ethanol (5 mL). The resulting mixture was heated at 80° C. for 4 h. TLC indicated a complete conversion. Work-up: the reaction solution was concentrated in vacuo, to afford 0.5 g (crude) of the product as a brown solid, which was used in the next step without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.C([O:14][C:15]([C@H:17]1[CH2:21][CH2:20][C@@H:19]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=2)[NH:18]1)=O)C.[OH-].[Na+]>O>[F:28][C:26]1[CH:27]=[C:22]([C@H:19]2[NH:18][C@@H:17]([CH2:15][OH:14])[CH2:21][CH2:20]2)[CH:23]=[C:24]([F:30])[C:25]=1[F:29]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: -15 °C
Reaction time: 19 h
Yield: 97.5 %

Procedure:
LAH (483 mg) was added to a THF solution (50 mL) of (2R,5S)-5-(3,4,5-trifluorophenyl)pyrrolidine-2-carboxylic acid ethyl ester (2.91 g) over 1 hr at −15° C. The resulting reaction solution was stirred at −15° C. for 19 hr. To the reaction solution, water (0.5 mL), a 5 N sodium hydroxide aqueous solution (0.5 mL), and water (1.5 mL) were added in this order. The resulting mixture was stirred at room temperature for 30 min and then filtered through Celite. The filtrate was concentrated under reduced pressure to give 2.4 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[CH2:3]([CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[CH2:2][CH2:1][CH2:5][CH3:4]
Reactant: O=C1CCCC1
Agent: [Pd]
Product: CCCCCC1CCCC1=O
Temperature: 25 °C
Yield: 108.4 %

Procedure:
A 3-L reaction flask was charged with cyclopentanone (500 g, 6 mol), water (H2O) (500 mL) and sodium hydroxide (NaOH) (10 g, 0.25 mol). Valeraldehyde (430 g, 5 mol) was fed into the reaction flask over 3 hours while the temperature was maintained at 25-30° C. After the feeding was completed, the reaction was aged for 2 hours and neutralized with hydrochloric acid (HCl) (30 g, 0.3 mol) while the temperature was maintained at 25-30° C. The reaction mass was further aged for 2 hours. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (NaHCO3) (200 mL). The obtained crude product was fractionated to provide 2-pentylidene-cyclopentanone (523 g) having a boiling point of 122° C. at 3 mmHg A 1-L zipper autoclave was charged with 2-pentylidine cyclopentanone (523 g) and palladium on carbon (Pd/C) (2 g). The autoclave was purged three times with nitrogen followed by three times with hydrogen. The autoclave agitator was then turned on to 1500 rpm and the pressure was set to 100 psi. The reaction was allowed to exotherm to about 120° C. and maintained at this temperature for 2 hours. The autoclave was cooled to an ambient temperature. The hydrogen was then vented and the autoclave was subsequently purged three times with nitrogen. The Pd/C was removed by filtration through Celite®. The crude product 2-pentyl-cyclopentanone (520 g) was obtained and used in following steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>C1(C)C=CC=CC=1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:1][C:2]1[C:12]([CH:18]=[CH2:19])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc([Si](C)(C)C)c(C(=O)NCC)c1Cl
Reaction time: 24 h
Yield: 21.3 %

Procedure:
To a solution of the compound of Example 239 (0.382 g, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) and 2.6-di-t-butyl-4-methylphenol (1.5 mg) in toluene (10 mL) was added vinyltributyltin (0.349 g, 1.1 mmol). The light yellow solution was heated at reflux for 24 h, additional tetrakis(triphenylphosphine)palladium(0) (15 mg) was added, and reflux was continued for 24 h. The cool mixture was diluted with ether, filtered through Celite, concentrated and purified by RC (ethyl acetate/hexanes). The product was further purified by recrystallization from pentane to afford the title compound as white needles (0.060 g, 21%). m.p. 127°-128° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=O)[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[H][H].[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:15]=1)=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](Cc1cccc(OCC(=O)c2ccc3ccccc3c2)c1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(OCCc2ccc3ccccc3c2)c1)C(=O)O
Yield: 35.7 %

Procedure:
Palladium hydroxide carbon (50% water content, 180 mg) was added to a solution of N-t-butoxycarbonyl-3-[(2-naphthoyl)methoxy]-L-phenylalanine methyl ester (400 mg, 0.863 mmol) in methanol (13 ml) and the mixture was stirred in hydrogen stream at room temperature for 20 hrs. The catalyst was filtered off and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=7) to give N-t-butoxycarbonyl-3-[2-[2-(5,6,7,8-tetrahydro-naphthyl)]ethoxy]-L-phenylalanine methyl ester (132 mg, 34%) and methyl ester of N-t-butoxycarbonyl-3-[2-(2-naphthyl)ethoxy]-L-phenylalanine (134 mg, 34%) (in turn of elution).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH3:26])=[CH:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:30]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]=[O:30])=[CH:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc2c(c1)C(C=O)=CC(C)(C)N2C(=O)OC(C)(C)C
Yield: 60.3 %

Procedure:
A mixture of 1.6 g of 6-(2-methoxyphenyl)-2,2,4-trimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester, 20 mL of 1,4-dioxane, and 1.4 g of selenium dioxide was refluxed for half an hour. Another 1.4 g portion of selenium dioxide was added. The reaction was allowed to reflux for 6 hours. The reaction mixture was then filtered through diatomaceous earth and the residue was rinsed with EtOAc. The solvent was evaporated in vacuo and the residue was purified by flash chromatography to yield 1 g of 4-formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17](OC)=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=CC=1.C1([C:27]2C3C(=C(CO)C=CC=3)C=C[N:28]=2)C=CC=CC=1>>[CH:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:27]#[N:28])[C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:4][CH2:5][CH2:6]1
Reactant: OCc1cccc2c(-c3ccccc3)nccc12
Reactant: COC(=O)c1cccc2c(-c3ccccc3)nccc12
Product: N#CCc1cccc2c(C3CCC3)nccc12

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and cyclobutanecarbonyl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-cyclobutylcarbonylamino-2-(2-hydroxymethylphenyl)ethane as in oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-cyclobutylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-cyclobutylisoquinoline-5-acetic acid having a decomposition point of 202.8° to 209.8° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8](=[O:10])[O:9][C:5]=2[CH:4]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO>[ClH:1].[F:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:15][CH2:16]3)[C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: O=C1CCOCC1
Reactant: O=c1oc2cc(F)ccc2n1C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CO
Product: O=c1oc2cc(F)ccc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one hydrochloride D6 (270 mg), tetrahydropyran-4-one (200 mg), and titanium tetraisopropoxide (0.6 mL) was stirred at room temperature for 1 h and then methanol (4 mL) and sodium cyanoborohydride (120 mg) were added. After a further 2 h the product was isolated by SCX chromatography and further purified by chromatography on silica gel eluting with 0-10% 2M methanolic ammonia-dichloromethane. Conversion to the hydrochloride salt gave 6-fluoro-3-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride E2 (40 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.ClC[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br>CN(C)C=O.C(O)CCC.O>[BrH:1].[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: COc1ccc(CCCCCCCCCCl)cc1
Reactant: OCc1ccc(O)c(Br)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Solvent: CN(C)C=O
Product: COc1ccc(CCCCCCCCOc2ccc(CO)nc2Br)cc1
Temperature: 25 °C

Procedure:
The crude 2-bromo-3-hydroxy-6-hydroxymethylpyridine (vide supra, 1.12 mol) was dissolved in dimethyl formamide (1150 ml) at 60° C. 1-Chloro-8-(4-anisyl)-octane (342 g, 1.34 mmol) and potassium carbonate (388 g, 2.81 mol) were added. It was found to be important that the potassium carbonate was ground to as fine a powder as possible. The mixture was stirred vigorously and heated to 90°-95° C. until the assay of 2-bromo-3-hydroxy-6-hydroxymethylpyridine (by HPLC) fell below 3% (approx 5 h). The mixture was then cooled to room temperature, poured into water (10 L) and extracted with ethyl acetate (3×670 ml). The combined ethyl acetate extracts were washed with water (2×500 ml) and dried before being evaporated to dryness. The crude reaction product was dissolved in butan-1-ol (2700 ml) and hydrogen bromide gas (120 g) passed through the solution keeping the temperature below 70° C. After allowing the mixture to cool to 10° C. with vigorous stirring the solid product was filtered and washed with ethyl acetate (2×500 ml). The solid product was dried under vacuum at 60° C. for 4 days. Yield 421 g, 75%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[CH2:16]([O:18][CH2:19][C:20](O)=[O:21])[CH3:17].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.O>[CH2:16]([O:18][CH2:19][C:20]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:21])[CH3:17]
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: CCOCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CCOCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 25 mL of dichloromethane was cooled to 0° C. and was successively treated with ethoxyacetic acid (0.26 mL, 1.1 eq.), dimethylaminopyridine (30 mg, 0.1 eq.) and dicyclohexylcarbodiimide (560 mg, 1.1 eq.). The reaction mixture was stirred at 0° C. for two hours then at room temperature for two hours, diluted with 25 mL water and extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting solid/oil was triturated in ether, the solid removed and the volatiles removed in vacuo, to give 674 mg (95%) of 2-ethoxy-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (35) as a pale yellow solid, which was used without purification.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:37])([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:37])([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCC(O)(CC)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CCC(O)(CC)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 74.5 %

Procedure:
A mixture of 3-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-pentan-3-ol (220 mg, 0.43 mmol) in ethanol (6 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 1.5 mL) was heated at 50° C. for 48 h. The mixture diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-pentan-3-ol (120 mg, 75%) which was used in the next step without further purification: LC/MS m/e calcd for C25H30N2O [M+H]+ 375.53, observed 375.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:13]([NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:15])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1nnn[nH]1
Reactant: COc1nc2ccccc2nc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1nc2ccccc2nc1C(=O)Nc1nnn[nH]1

Procedure:
3Methoxy-2-quinoxalinecarboxylic acid (1.5 g) and N,N-carbonyldiimidazole (1.2 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.7 g) in dimethylformamide (5 ml) was added and the solution was heated under reflux for 1 hour. The crystalline solid was collected and stirred with dilute hydrochloric acid (25 ml., 2N) and the solid was filtered off and dried. It had m.p. 260° (d) (45%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])[CH2:21][N:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[CH2:21][N:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[CH:10][CH:9]=1
Reactant: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)N1CCC(c2ccc(N)cc2)CC1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.11 g) (59%) of 1-[4-(4-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 10.54 (s, 1H), 7.52 (d, 2H, J=8.5 Hz), 7.20 (d, 2H, J=8.5 Hz), 4.10 (s, 2H), 3.34-3.37 (m, 2H), 2.97-3.12 (m, 3H), 2.85 (s, 6H), 1.88-1.91 (m, 2H), 1.69-1.78 (m, 2H).