Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH2:23][CH3:24])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>ClCCl>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][CH3:24])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC1CN(C(C)(C)C)CC2(CCNCC2)O1
Reaction time: 0.25 h
Yield: 104 %

Procedure:
Tert-butyl 8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (530 mg, 1.56 mmol) was dissolved in dichloromethane and treated with a solution of HCl in dioxane (8.0 mL of 4 M, 33 mmol) and stirred for 15 min. The reaction mixture was diluted with dichloromethane and washed with 1:1 saturated NaHCO3/1 M NaOH. The organic layer was dried over Na2SO4, filtered and concentrated to provide 8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane (390 mg, 99%) as an oily solid. ESI-MS m/z calc. 240.2. found 241.3 (M+1)+; Retention time: 0.21 minutes (3 min run).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:34]1(=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:34]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCC1
Reactant: Brc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Cc3ccccc3OCc3ccccc3)cc2)CCCC1
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 294 mL) was added dropwise to a solution of 1-benzyloxy-2-(4-bromobenzyl)benzene (1.5 g, 4.25 mmol) in THF (16.5 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this mixture, a solution of cyclopentanone (357 mg, 4.25 mmol) in THF (4 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for 50 minutes and at 0° C. for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (1.14 g, 75%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([CH:9]1[CH2:14][CH2:13][N:12](C(C(F)(F)F)=O)[CH2:11][CH2:10]1)=[O:8])([O-:3])=[O:2].[N+](C1C=CC=CC=1C(C1CCN(C(C(F)(F)F)=O)CC1)=O)([O-])=O.[ClH:47]>C(O)(C)C>[ClH:47].[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C(c1ccccc1[N+](=O)[O-])C1CCN(C(=O)C(F)(F)F)CC1
Solvent: CC(C)O
Product: O=C(c1cccc([N+](=O)[O-])c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
4-(3-nitrobenzoyl)-1-trifluoromethylcarbonylpiperidine and 4-(2-nitrobenzoyl)-1-trifluoromethylcarbonylpiperidine [67(m):33(o)] mixture (40.36 g, 0.122 mol) was heated with reflux in isopropanol (1.39 L) containing HCl 37% (209 mL) for 18 h. The reaction was monitored by TLC [silica gel/ethyl acetate-hexane (2:3)]. The resulting solution was allowed to cool to room temperature and the crystallization occurred at Tmass=35° C. Then the suspension was post-agitated for 3 h at room temperature. The precipitate was collected by filtration, washed with ethanol (100 mL) and ethyl ether (100 mL) and dried under vacuum at 50° C. to give pure 4-(3-nitrobenzoyl)piperidine HCl as a pale yellow solid (17.81 g, 54%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH:25]6[CH2:27][CH2:26]6)[N:20]=5)[CH:17]=4)[N:12](C4CCCCO4)[N:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH:25]6[CH2:27][CH2:26]6)[N:20]=5)[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1cc2c(cc1-c1cncc(C3CC3)n1)c(-c1cncc(C3CC3)n1)nn2C1CCCCO1
Agent: Cl
Solvent: CO
Product: c1cc2[nH]nc(-c3cncc(C4CC4)n3)c2cc1-c1cncc(C2CC2)n1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A solution of 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (74 mg, 0.17 mmol) and HCl (5-6 M in IPA, 3.4 mL, 16.9 mmol) in 5 mL of MeOH was heated at 80° C. for 90 min. The crude reaction was cooled to RT and concentrated to a yellow solid that was slurried with a 1\1 mixture of DCM\MeOH (12 mL) and applied to a pre-washed (45 mL MeOH) of Si-propylsulfonic acid (12 g, Silicycle, Cat# R51230B). The column was washed with MeOH (35 mL). The compound was released with 35 mL of 2 M NH3 in MeOH. The crude product was purified by silica gel chromatography, eluting with a gradient of 0-75% EtOAc in hexanes, to provide the title compound (20 mg, 0.056 mmol, 33% yield) as a white solid. MS (ESI, pos. ion) m/z: 355.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.09-9.16 (m, 2H), 8.97 (s, 1H), 8.60 (d, J=16.63 Hz, 2H), 8.15 (dt, J=8.80, 0.88 Hz, 1H), 7.74 (d, J=8.80 Hz, 1H), 2.32-2.38 (m, 1H), 2.25-2.31 (m, 1H), 1.16-1.26 (m, 6H), 1.09-1.15 (m, 2H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH:24]([OH:42])[CH:25]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24](=[O:42])[CH:25]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(O)C(CCc1ccccc1)CCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 0.22 g (1.0 mmol) of pyridinium chlorochromate in anhydrous CH2Cl2 (15 mL) was added dropwise a solution of 0.2 g (0.5 mmol) of 10a in anhydrous CH2Cl2 (5 mL), and the mixture was stirred at an ambient temperature for 16 hours. The solution was filtered and the resulting solution was evaporated to a yellow oil which was subject to column chromatography (EtOAc/Hexanes, 1:3) to yield 0.16 g (76.2%) of 11a as a clear oil. TLC Rf=0.5 (EtOAc/Hexanes, 1:3)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16][NH2:17].C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH2:16][NH:17][CH2:4][C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1ccc(Br)c(CBr)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-5-fluoro benzyl bromide (0.5 g, 1.86 mmol) and 3,5-bis(trifluoromethyl)benzylamine (0.45 g, 1.86 mmol) in methylene chloride (10 ml) at 0° C., triethyl amine (0.39 ml, 2.80 mmol) was added. The solution was slowly warmed to room temperature and stirred for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (2:8) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 2H), 7.80 (s, 1H), 7.53 (dd, J=8.8, 5.3 Hz, 1H), 7.18 (dd, J=9, 3.3 Hz, 111), 6.91 (dt, J=8.5, 3.3 Hz, 1H), 3.98 (s, 2H), 3.90 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.[C:12]1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=CC=C[CH:13]=1.C([Mg]Br)CC.S(=O)(=O)(O)O>[Ni].C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Ni+2].O1CCCC1.C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH2:13]([C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:11]=[C:2]([Cl:1])[N:3]=2)[N:6]=1)[CH2:12][CH3:17]
Reactant: Clc1cn2nc(Cl)ccc2n1
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Ni+2]
Agent: [Ni]
Agent: CCC[Mg]Br
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: CCCc1ccc2nc(Cl)cn2n1
Yield: 94 %

Procedure:
Into a 500 mL four-necked separable flask purged with nitrogen, 20.17 g of 2,6-dichloroimidazo[1,2-b]pyridazine (content: 99.2% by weight) and 190.5 g of xylene were charged to prepare a xylene solution containing 2,6-dichloroimidazo[1,2-b]pyridazine. The solution obtained by mixing 4 mL of xylene and 0.22 g of 1,3-bis(diphenylphosphino)propane and 0.62 g of a toluene solution of nickel naphthenate (II) (content: 5% by weight) were mixed to prepare a solution containing a nickel catalyst. The xylene solution containing 2,6-dichloroimidazo[1,2-b]pyridazine and the solution containing a nickel catalyst were mixed, and to the resultant mixture, 63.4 g of a tetrahydrofuran solution of n-propylmagnesium bromide (content: 22.2% by weight) was added dropwise over about 2 hours at an inner temperature of 20 to 30° C. to effect reaction. After completion of the reaction, the reaction mixture was added dropwise into a mixture of 40.4 g of 3% by weight aqueous sulfuric acid solution and 1 g of Radiolite (which was manufactured by Showa Chemical Industry Co., LTD.). After that, the resultant mixture was stirred and filtrated. The organic layer was separated from the filtrate obtained and washed twice with about 40 g of water. The organic layer after washing was concentrated to obtain 20.9 g of 6-n-propyl-2-chloroimidazo[1,2-b]pyridazine (purity: 93.2%). Yield: 94%
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:12])[CH3:11]
Reactant: OC1CN2CCC1CC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CN2CCC1CC2
Yield: 95 %

Procedure:
A racemic mixture of (RS) 3-quinuclidinol was dissolved in acetic anhydride and refluxed for three hours to yield a racemic mixture of (RS) 3-acetoxy quinuclidine (b.p. 61°-63° C./0.26 mm Hg; 95% yield). To a boiling solution of 28.28 g of this racemic mixture was added a boiling solution of 25.1 g L-(+)-tartaric acid dissolved in 60 ml of 80% ethanol. The solution was allowed to cool to room temperature, then allowed to stand for several hours, yielding crystals of the (+) hydrogen tartrate salt of 3-acetoxy quinuclidine. This salt was recrystallized three times in 80% ethanol to give 16.77 g of colorless crystals (m.p. 93°-96° C. (froths)). In like manner, the free base obtained from the first mother liquor was then treated with R(-)-tartaric acid and recrystallized to yield 14.5 g of colorless crystals of the (-) hydrogen tartrate salt (m.p. 93°-97° C. (froths)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][CH3:13].C(N(CC)CC)C.C(Cl)(Cl)Cl.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=1
Reactant: CNCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
To a mixture of 0.42 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methylamino)propyloxy)benzene, 0.18 ml of triethylamine and 10 ml of chloroform was added 0.18 ml of 4-(trifluoromethyl)benzoyl chloride, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(N-methyl-4-(trifluoromethyl)benzamido)propyloxy)benzene (55% yield), nD24.5 1.5461.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([NH:31][CH2:30][CH2:29][C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([C:19]([F:33])([F:18])[F:32])[CH:21]=3)[NH:25][CH:24]=2)=[O:12])[CH:6]=1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(C(F)(F)F)cc12)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
A mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.08 g, 0.334 mmol), 2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine (0.080 g; 0.334 mmol), HATU (0.127 g; 0.334 mmol) and N,N diisopropylethylamine (0.144 mL; 0.836 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.013 g (9%) of 5-(2,5-difluorobenzyl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>O1CCCC1>[S:1]1[CH:5]=[C:4]([C:6]([CH:8]=[CH:9][C:10]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:12])=[O:7])[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)C=CC(=O)c1csc2ccccc12
Solvent: C1CCOC1
Product: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1csc2ccccc12

Procedure:
As for Example 1, 3-(benzo[b]thien-3-ylcarbonyl)acrylic acid (0.01 mole) is coupled to L-proline (0.01 mole) with N,N'-carbonyldiimidazole in tetrahydrofuran to give 1-[3-(benzo[b]thien-3-ylcarbonyl)acryloyl]-L-proline.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=C)[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:29])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cccc(C2(C)CCN(C(=O)CCCCC)CC2C)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCC(=O)N1CCC(C)(c2cccc(C=O)c2)C(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-hexanoyl-3,4-dimethyl-4-(3-vinylphenyl)piperidine (Preparation 8, 2.4 g, 7.67 mmol) in acetone (20 mL) at room temperature was added water (5 mL), 4-methylmorpholine N-oxide (1.1 g, 9.20 mmol) and finally osmium tetroxide (3.83 mL, 2.5 wt % solution in tert-butanol). The yellow solution was stirred at room temperature for 1 hour and then sodium periodate (4.92 g, 23.0 mmol) was added in one portion. After stirring the reaction for 3 hours a heavy precipitate had developed and the reaction mixture was filtered through Celite®, washing with acetone. The filtrate was concentrated in vacuo, the crude oil was dissolved in dichloromethane, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane (1:1). The title compound was isolated as clear oil (2.0 g).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C@H:32](N)[CH3:33])[CH:29]=[CH:30][CH:31]=1.[BH4-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][CH2:10][NH:11][C@@H:32]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=2)[CH3:33])=[CH:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: CC(C)c1ccc(C=CC#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC=Cc2ccc(C(C)C)cc2)c1

Procedure:
In a similar fashion, 4-isopropylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(4-isopropylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12E, as a clear, colorless oil; m/z (rel. int.) 309 (M+, 9), 294 (7),174 (98),159 (22),135 (80), 117 (100),105 (35), 91 (37), 77 (19).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:8]=[C:7]2[N:21]=[N+]=[N-])([O-])=O.O>C(OCC)(=O)C.C(O)C>[F:20][C:16]1[CH:15]=[C:14]([C:9]2[CH:8]=[C:7]([NH2:21])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([NH2:1])[CH:5]=3)[N:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=Nc1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc2nc(-c3cccc(F)c3)cc(N)c2c1
Yield: 88 %

Procedure:
6-Nitro-4-azido-2-(3-fluorophenyl)-quinoline was placed in a 500 mL three neck flask equipped with a condenser, magnetic stirrer, nitrogen inlet gas outlet and a silicone oil heating bath and suspended in 250 mL of ethyl acetate and 50 mL of ethanol. The mixture was stirred, heated to reflux, 20 g (89 mmoles, 6 equiv.) of stannous chloride dihydrate cautiously added portionwise over 40 min, and the mixture was heated for an additional 2 hr. At the end of this time, the mixture was cooled and poured into 500 mL of water. The pH was cautiously adjusted to 9.0 and the solution filtered. Solids were washed with 100 mL of ethyl acetate, the filtrates combined and the aqueous layer twice extracted with 200 mL of ethyl acetate. The organic layers were combined dried over Na2SO4, filtered and concentrated. The product was chromatographed on a silica gel column, using 10% methanol in ethyl acetate as eluent, and was then recrystallized from methylene chloride and hexane to give 3.6 g (88%) of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1>C(O)C>[NH:2]([C:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1)[NH2:3]
Reactant: CSc1nc(Cl)c2ncccc2n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1nc(NN)c2ncccc2n1
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Hydrazine hydrate (13.0 mL (13.3 g, 237 mmol)) was added at ambient temperature with stirring to a mixture of 16.7 g (79 mmol) of 4-chloro-2-methylthiopyrido[3,2-d]pyrimidine in 200 mL of ethanol. There was a slight exotherm and the mixture thickened and then became more mobile again. After 30 min, the volatile components were removed by evaporation under reduced pressure. The residue was diluted with water and the solids were recovered by filtration, washed with ether, and dried to obtain 15.7 g of the title compound as a brown powder melting above 300° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:26]CC2C=CC=CC=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([F:25])[CH:12]=1)[CH:6]=[CH:5]2>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[CH:6]=[CH:5][C:4]=2[C:3]=1[OH:26]
Reactant: Fc1cc(-n2ccc3c(OCc4ccccc4)c(F)ccc32)ccc1OCc1ccccc1
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ccc3c(O)c(F)ccc32)cc1F

Procedure:
A solution of 5-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole (D7) (143 mg) in ethyl acetate (8 mL) was passed through the H-cube at 1 mL/min with 1 Bar H2 pressure. The solution was evaporated and purified by chromatography on silica gel (elution with 0-50% ethyl acetate in hexane) to give the title compound (E5) as an off white solid (65 mg).
Reaction SMILES: [C:1]1([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:40](O)[CH3:41]>S(=O)(=O)(O)O>[CH2:40]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)[CH3:41]
Reactant: CCO
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Reaction time: 3 h

Procedure:
590 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 80 ml of ethanol and 12 drops of concentrated sulfuric acid was added. The reaction solution was boiled for 3 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 381 mg. MS (ES+): m/e=580.3 (M+H)+.