Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH:10]=[CH:11][C:12](=[O:21])[CH2:13]4>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@@H]1C=CC(=O)C3
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@@H]1CCC(=O)C3

Procedure:
A 2.0 g sample of 7,8-didehydro-3-methoxy-17-methylmorphinan-6-one (prepared as described by SAWA et al., Tetrahedron 20: 2247 [1964]) was dissolved in 300 ml of 95% ethanol and hydrogenated at 50 psi for 4 hours using 150 mg of 10% Pd/C catalyst. The solution was filtered and evaporated to yield a crystalline residue. The product was recrystallized from ethanol to give 760 mg of product, mp 187°-188.5° C. (lit. mp 188°-189° C.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:42])[O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CCOCC>[CH:36]1([O:35][C:34](=[O:42])[NH:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: O=C(Cl)OC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CNC(=O)OC2CCCCC2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Example 42 (90 mg, 0.26 mmol), iPr2NEt (0.078 mL, 0.45 mmol), and cyclohexyl carbonochloridate (51.2 mg, 0.315 mmol) in DCM (4 mL) was stirred at room temperature for 8 hours, diluted with Et2O, washed with sat NaHCO3 and brine, dried (MgSO4), filtered, concentrated, and chromatographed (17-25% EtOAc/DCM) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.60 (s, 1H), 8.32 (dd, J=7.8, 1.4 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.97-8.03 (m, 1H), 7.91 (td, J=7.5, 1.2 Hz, 1H), 7.60-7.65 (m, 1H), 7.41 (s, 4H), 4.47-4.51 (m, 3H), 3.67 (s, 2H), 1.58-1.84 (m, 4H), 1.41-1.54 (m, 1H), 1.10-1.35 (m, 4H); MS (ESI−) M/Z 467 (M−H)−.
Reaction SMILES: [C:1]([S:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.CO>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:7][CH:8]=1
Reactant: CC(C)(C)Sc1ccc(C#N)cn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Sc1ccc(CN)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Use a method similar to the General Procedure 6-5 to react 6-(tert-butylthio)nicotinonitrile (4.4 g, 22.7 mmol) in anhydrous THF (25 mL) with 1M BH3-THF complex in THF (25 mL, 25 mmol). Add 5M aqueous HCl (10 mL) cautiously and stir the mixture overnight at room temperature. Extract into EtOAc, wash with brine, dry over MgSO4 and concentrate in vacuo to give an orange solid. Dissolve the crude mixture in methanol and filter through an SCX column eluting with methanol followed by 3M ammonia in methanol to obtain the title compound (2.74 g, 61%). MS (ES+) m/z: 197 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24](OCC)=[O:25].Cl.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24](=[O:25])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: Cl
Product: O=C(Nc1ccccc1)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Temperature: 180 °C
Reaction time: 3 h

Procedure:
Dissolving 280 mg of 7-hydroxy-6-ethoxycarbonyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine in 3 ml of aniline, the mixture was stirred for 3 hours at 180° C. After allowing to cool, 10% hydrochloric acid was added, the precipitate was filtered, washed with water and dried, and the title compound was obtained (220 mg, 68%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Li].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C[Mg]I>O1CCCC1.C(OCC)C.[Cl-].[NH4+].O>[C:16]([C:15]1([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[CH2:23][CH:22]([OH:24])[CH2:20]1)#[N:17]
Reactant: BrCC1CO1
Reactant: COc1ccc(CC#N)cc1OC1CCCC1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2(C#N)CC(O)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (prepared as described in U.S. Pat. No. 5,631,284) (12.65 g, 54.7 mmol) in tetrahydrofuran (400 mL) and examethylphosphoramide (16 mL) at -78° C. under an argon atmosphere was first treated dropwise over 75 min with 1.4 M methyllithium in diethyl ether (47 mL, 65.6 mmol), then with epibromohydrin (5.6 mL, 65.6 mmol). The reaction was allowed to warm to room temperature and was stirred for 3 h, then was recooled to -78° C. and was treated dropwise over 0.5 h with 3.0 M methylmagnesium iodide in diethyl ether. The reaction was stirred at room temperature for 20 h, diluted with aqueous ammonium chloride and water, and was extracted three times with tertbutyl methyl ether. The organic extract was dried (magnesium sulfate), was evaporated and was partially purified by flash chromatography, eluting with 35:65 ethyl acetate:hexanes to provide a mixture of cis- and trans-3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclobutan-1-ol and cis- and trans-2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclopropylmethanol (~9: 1, by 1H-NMR) as a dark orange oil (10.01 g, 64%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]([C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4][C:3]=1[CH3:24].C([O-])=O.[NH4+:28]>C(O)C>[C:9]1([C:8]2[NH:28][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:5]3[C:6]=2[CH2:7][C:2]([CH3:1])=[C:3]([CH3:24])[CH2:4]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: CC1=C(C)CC(C(=O)c2ccccc2)C(C(=O)c2ccccc2)C1
Agent: O=C[O-]
Solvent: CCO
Product: CC1=C(C)Cc2c(-c3ccccc3)[nH]c(-c3ccccc3)c2C1

Procedure:
A solution containing 4.46 g of 1,2-dimethyl-4,5-dibenzoylcyclohexene (Preparation 1) and 8.81 g of ammonium formate in 70 ml of anhydrous ethanol is heated at reflux for 24 hours. A precipitate is obtained which is filtered off and then dissolved in dichloromethane. The organic phase is washed with water, dried over calcium sulphate and concentrated to allow the isolation of 4 g of the expected product.
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:18][C:19]([NH2:21])=[O:20])=[C:15]([CH:17]=1)[NH2:16])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([NH:26][C:27](=[N:30][C:31]([O:33][CH3:34])=[O:32])SC)=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:34][O:33][C:31]([NH:30][C:27]([NH:26][C:24]([O:23][CH3:22])=[O:25])=[N:16][C:15]1[CH:17]=[C:11]([S:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:9])=[O:10])[CH:12]=[CH:13][C:14]=1[NH:18][C:19]([NH2:21])=[O:20])=[O:32]
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)NC(=Nc1cc(S(=O)(=O)Oc2ccccc2)ccc1NC(N)=O)NC(=O)OC

Procedure:
15.3 g of 5-phenoxysulfonyl-2-ureidoaniline, 12 g of N,N'-bismethoxycarbonyl-S-methylisothiourea and 100 mg of p-toluenesulfonic acid in 80 ml of methanol and 80 ml of ethyl acetate are stirred under reflux for four hours. After cooling down, the solid is filtered off with suction and washed with ethyl acetate and diisopropyl ether. For recrystallization, the solid is dissolved in dimethylformamide at about 50° C., treated with active charcoal, filtered, ethyl acetate and diisopropyl ether are added and crystallization is allowed to occur, melting point 193° C., decomposition.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O.[NH2:29][NH2:30].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:29][N:30]=[C:19]([CH2:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:3]=3[C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CC1CCOCC1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(CC3CCOCC3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-(tetrahydro-2H-pyran-4-ylacetyl)-1,8-naphthyridin-2(1H)-one (120 mg, 0.33 mmol) produced in Synthesis Example 40 in DMF (2 mL) was added hydrazine monohydrate (purity of 80%, 53 μL), and the mixture was stirred at 110to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogen carbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 5-phenyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (66 mg, yield 55%).
Reaction SMILES: ClC1C=CC(N2C([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=[O:19])=C3C(CCCC3)=N2)=CC=1.N1C=CC=CC=1.FC(F)(F)C(O[C:38]1[C:43]([F:44])=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48])=O.C1COCC1.CS(C)=O>CN(C=O)C>[F:44][C:43]1[C:38]([O:20][C:18](=[O:19])[CH2:17][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:39]([F:48])[C:40]([F:47])=[C:41]([F:46])[C:42]=1[F:45]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CC1CCCCC1)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (4.5 g, 12.1 mmol; example 5.1) in DMF (45 ml) was added pyridine (1.07 ml, 13.3 mmol) and pentafluorophenyl trifluoroacetate (4.16 ml, 24.1 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 12 h, poured onto ice water/0.1 N HCl 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/sat. aqueous NaHCO3 solution 1/1, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give 2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester as a yellow oil (9 g, 16.7 mmol; quant.) which was directly used in the next reaction step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49](B4OC(C)(C)C(C)(C)O4)[CH:50]=3)[CH:45]=2)=[CH:42][N:43]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C([O-])(=O)C.[K+]>COCCOC.O.C(OCC)(=O)C.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:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:49]3[CH:48]=[CH:47][C:46]4[C:51](=[CH:52][CH:53]=[C:44]([C:41]5[NH:40][C:39]([CH:35]6[CH2:36][CH2:37][CH2:38][N:34]6[C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[N:43][CH:42]=5)[CH:45]=4)[CH:50]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1
Temperature: 90 °C
Yield: 33.6 %

Procedure:
The mixture of 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (356 mg, 0.85 mmol), 2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (501 mg, 1.02 mmol), tetrakis(triphenylphosphine)palladium (99 mg, 0.08 mmol) and potassium acetate (425 mg, 3.07 mmol) in 7 mL 1,2-dimethoxyethane and 2 mL water was heated to 90° C. for 2 hour. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(4-{6-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, yield 33%) and the amide product. LCMS-ESI−: calc'd for C41H45N7O4: 699.84. Found: 700.2 (M+H+).
Reaction SMILES: CN(C)CCN(C)C.C(=O)=O.C([Li])(CC)C.C1CCCCC1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27]([OH:29])=[O:28].[Cl:34]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:34][C:25]1[C:24]([Cl:23])=[C:32]([F:33])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(Cl)c1Cl
Temperature: -85 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To an oven-dried, N2-purged 1-L, round-bottomed flask containing a large magnetic stir bar were added via syringe anhydrous tetrahydrofuran (200 mL) and tetramethylethylenediamine (11.3 mL, 8.72 g, 75.0 mmol). The flask was cooled to −85° C. (dry ice/anhydrous ether slurry) and the sec-butyllithium/cyclohexane solution (53.6 mL of 1.4 M solution, 75.0 mmol) was added via syringe. A solution of commercially available 3-chloro-4-fluorobenzoic acid (5.24 g, 30 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the reaction via syringe. The resulting orange/brown slurry was stirred at −85° C. for 2 hours. A solution of hexachloroethane (28.4 g, 120 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to the reaction mixture. The mixture was stirred at −85° C. for 1 hour and then allowed to warm to room temperature over 4 hours. The solvents/volatiles were removed by rotary evaporator to give a brown semi-solid. Water (150 mL) was added. The mixture was transferred to a separatory funnel and washed with ether (2×100 mL). Hydrochloric acid (1 N) was added via pipette to adjust the pH to ˜1. The mixture was extracted with ethyl acetate (4×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a tan solid. The product was recrystallized from ethyl acetate/hexanes to give 4.36 g (70%) of the title compound as a fine white powder. MS (ESI−) m/z 206.9 (M−H); 1H NMR (DMSO-d6) δ 7.54 (dd, J=8.8, 8.8 Hz, 1H), 7.85 (dd, J=8.8, 5.8 Hz, 1H), 13.72 (br s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].N[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+].O1CCCC1>O>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1ccc(S(=O)(=O)CCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
2.5 g of 4-diethylaminobenzenesulphonyl chloride are added to a solution comprising 1.17 g of 5-aminovaleric acid and 1.2 g of sodium hydroxide dissolved in 12 cm3 of water, followed by the addition of 12 cm3 of tetrahydrofuran in order to obtain a solution. The mixture is kept stirring for 2 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 2.2 g of expected product are obtained. M.p. 106°-108° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 109°-110° C., is obtained.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([N:19]([C:21](=[O:23])[CH3:22])[OH:20])[CH3:18])[C:12]=1[Cl:24].Cl>[OH-].[K+]>[C:21]([N:19]([OH:20])[CH:17]([C:13]1[C:12]([Cl:24])=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:25])=[O:2])[CH:16]=[CH:15][CH:14]=1)[CH3:18])(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccccc1Nc1cccc(C(C)N(O)C(C)=O)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(=O)N(O)C(C)c1cccc(Nc2ccccc2C(=O)O)c1Cl
Yield: 30.3 %

Procedure:
2-[[3-[1-(Acetylhydroxyamino)ethyl]-2-chlorophenyl]amino]benzoic acid methyl ester (0.24 g, 0.7 mmol) is suspended in 150 mL of 1 N potassium hydroxide containing 10 mL methanol. The reaction mixture is stirred until all the solid is dissolved (about 2 hours). It is acidified to pH=1 with concentrated HCl and the resulting precipitate is collected by filtration. Recrystallization from ethyl acetate gives 2-[[3-[1-[acetylhydroxyamino)ethyl]-2-chlorophenyl]amino]benzoic acid (74 mg, 32 %) as a hydrate. mp=162-164° C. dec.
Reaction SMILES: [N:1]1([C@@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:31]1C=CC=C[CH:32]=1>C(OCC)(=O)C.CN>[N:1]1([C@@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12][NH:31][CH3:32])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccncc1
Reactant: OC[C@@H](O)[C@H](c1cccs1)n1ccc2ccccc21
Agent: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CNC[C@@H](O)[C@H](c1cccs1)n1ccc2ccccc21
Reaction time: 16 h
Yield: 71 %

Procedure:
(2S,3R)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol (102 mg, 0.37 mmol) was dissolved in pyridine (1.5 mL), para-toluenesulfonyl chloride (88 mg, 0.46 mmol) was added and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of copper sulfate, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0%-100% ethyl acetate in hexane) to afford 140 mg that was immediately dissolved in methylamine (8M solution in ethanol, 15 mL) and stirred for 3 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, gradient 2%-10% methanol saturated with ammonia in chloroform) to give 65 mg (71%) of (1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol as a colorless oil. The freebase was dissolved in diethyl ether (5 mL) and treated with a 1 N ethereal solution of hydrochloric acid (0.23 mL, 0.23 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give (1R,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol hydrochloride. HRMS: calcd for C16H18N2OS+H+, 287.12126; found (ESI, [M+H]+), 287.1209
Reaction SMILES: Br.[CH:2]1([CH2:8][C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>>[CH:2]1([CH2:8][C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1CC1CCCCC1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](CC3CCCCC3)C2)o[nH]1
Reaction time: 8 h
Yield: 24.8 %

Procedure:
HBr (33% in acetic acid) (5 mL) was added to (2R,4R)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.28 g, 0.87 mmol). The reaction was stirred vigorously overnight. The solvent was evaporated. Purification using PrepLC (pH=11, small column, no sandwitching, sample dissolved in methanol/water (50/50), gradient 15-55, 20 minutes). The title compound (57 mg, 25%) was obtained. 1H NMR (400 MHz, cd3od) δ 0.78-0.95 (m, 2H), 1.17 (dd, 3H), 1.28-1.48 (m, 4H), 1.63 (dd, 6H), 2.04 (d, 1H), 2.12 (d, 1H), 2.85 (t, 1H), 2.96 (dd, 1H), 3.13 (s, 1H), 3.31 (d, 1H), 5.40 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][CH:4](C)[C:3]1=[O:9].Cl[CH2:12]C=CCCl.N.O>C1COCC1>[CH3:12][CH:7]1[CH2:6][CH2:5][CH2:4][C:3](=[O:9])[C:2]1([CH3:1])[CH3:10]
Reactant: CC1CCCC(C)(C)C1=O
Reactant: ClCC=CCCl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
28 g of 2,2,6-trimethyl-cyclohexanone are added dropwise to a suspension of Na vinylacetylide (prepared from 25 g of 1,4-dichlorobut-2-ene and 15 g of Na in liquid ammonia) in 200 ml of THF, whilst cooling, and the reaction mixture is stirred overnight at room temperature. 50 ml of water are then added, the aqueous phase is extracted with ether and the resulting organic phase is dried and concentrated. Subsequent fractional distillation gives 5.5 g of unconverted trimethylcyclohexanone and 20.7 g (corresponding to 68% of theory, based on ketone converted) of 2,2,6-trimethyl-1-(but-1'-yn-3'-en-1'-yl)-cyclohexanol of boiling point 62°-63° C/0.3 mm Hg and refractive index nD25 = 1.4982. Fragrance note: fresh, tart-woody, coniferous.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1CC[CH2:9][CH2:8]1.[N:12]([CH2:15][C@H:16]1[O:21][CH:20]=[CH:19][C@@H:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:17]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N+]=[N-]>CCOCC>[C:8]([NH:12][CH2:15][C@H:16]1[O:21][CH:20]=[CH:19][C@@H:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:17]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:7])[CH3:9]
Reactant: C1CCOC1
Reactant: [N-]=[N+]=NC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=O)NC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
Stir a suspension of 760 mg. of lithium aluminum hydride in 50 ml. of tetrahydrofuran and to this add dropwise a solution of 2.98 gm. of 6-azido-6-deoxy-3,4di-O-benzyl-D-glucal in 30 ml. of tetrahyrofuran. Heat the mixture under reflux for 4 hours, cool and add wet ether, filter evaporate the filtrate to a residue. To the residue add 3 ml. of acetic anhydride and 10 ml. of distilled pyridine, stir for 2 hours and remove the solvent, crystallize the residue in chloroform: hexane to obtain 6-acetamido-6-deoxy-3,4-di-O-benzyl-D-glucal [α]26D - 41.8° (EtOH); pmr (CDCl3) δ 1.86 (3H, s, COCH3), 3.65 (2H, m, -CH2 -N), 4.6 (2H, m, ArCH2), 4.75 (2H, m, Ar-CH2), 4.9 (1H, dd, J=3, 6Hz, H-2), 6.45 (1H, dd, J=1.5, 6Hz, H-1); ν max (nujol) 3250, 1640 cm-1.