Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][NH:5][C:4]2[CH:10]=[CH:11][S:12][C:3]1=2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1c[nH]c2ccsc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2ccsc2c1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carbonitrile (3.00 g, 17.0 mmol) and 25 mL of phosphorous oxychloride is heated at reflux for 10 minutes. The reaction mixture is cooled to room temperature and the dark solids are removed by filtration. The filtrate is poured into hexane and allowed to stand at room temperature. The solvent is decanted off and the residual oil is dissolved in ethyl acetate and the solution is washed with water. The organic layer is dried over magnesium sulfate, filtered and passed through silica gel. The filtrate is concentrated in vacuo to give 770 mg of the desired product as a dark orange solid. A portion of this material is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 7-chlorothieno[3,2-b]pyridine-6-carbonitrile as tan crystals, mp 110-111° C.; 1H NMR (DMSO-d6) δ 7.81 (d, J=5 Hz, 1H), 8.59 (d, J=5 Hz, 1H), 9.12 (s, 1H); MS 194.9 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16](CC2C=CC=CC=2)[CH2:15][CH2:14]1)=[O:12].CCOCC>C(O)C.[H][H].[Pd]>[ClH:1].[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)=[O:12]
Reactant: O=C(Cc1ccc(O)cc1O)N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C(Cc1ccc(O)cc1O)N1CCNCC1
Yield: 122.2 %

Procedure:
To a solution (10 ml) of 1-(2,4-dihydroxyphenyl-acetyl)-4-benzylpiperazine.hydrochloride (160 mg) obtained in Example 9, ii) in ethanol is added palladium-black (30 mg) to subject to catalytic reduction in hydrogen at 40° C. under twice atmospheric pressure for 10 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The glass-like substance obtained is digested with ether into powder. This is filtered and dried to obtain 1-(2,4-dihydroxyphenylacetyl)piperazine.hydrochloride (147 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]([NH:5][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[CH:6]([CH3:8])[CH3:7])=[O:9]
Reactant: O=S1(=O)CCCO1
Reactant: COC(=O)[C@@H](N)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NCCCS(=O)(=O)O)C(C)C
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of L-valine methylester in THF (25 mL) was slowly added 1,3-propanesultone (2.49 g, 19.9 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×30 mL). It was dried in the vacuum oven (50° C.) affording the title compound (2.52 g, 50%). 1H NMR (D2O, 500 MHz) δ ppm 3.92 (m, 1H), 3.75 (s, 3H), 3.13 (t, 2H, J=6.8 Hz), 2.88 (t, 2H, J=6.8 Hz), 2.24 (m, 1H), 2.06 (m, 2H)), 0.96 (d, 3H, J=6.8 Hz), 0.88 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 169.35, 65.85, 55.61, 48.14, 45.59, 29.48, 21.32, 18.25, 16.57. [α]D=+9.6° (c=0.0014 in water), ES-MS 254 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1Cn2c(=O)cnc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 103.3 %

Procedure:
(1S)-1-(Hydroxymethyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (750 mg, 3.42 mmol) was suspended in dry DCM (100 ml) at room temperature under argon and then treated with triethylamine (0.572 ml, 4.11 mmol). The mixture was then cooled using an ice-water bath. Methanesulfonyl chloride (0.293 ml, 3.76 mmol) was then added and the reaction was allowed to warm up to room temperature. After 50 minutes there was no starting material left so the mixture was washed with saturated NaHCO3 (100 ml). The aqueous layer was extracted with 20% MeOH/DCM (2×100 ml); the combined organic extracts were dried on magnesium sulphate, filtered and evaporated to afford the product as a brown foam (1.05 g, 90% purity by LCMS).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1>C(O)C>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH2:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Solvent: CCO
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a suspension of 8 (6.28 g, 20.0 mmol) in ethanol (200 mL) palladium on carbon (10%, wet, 0.63 g) was added and stirred under H2 at atmospheric pressure at room temperature for 18 h. Catalyst was filtered through a bed of Celite® and solvent was evaporated under reduced pressure to yield 15 as white solid (6.32 g, 100%): mp 63-65° C.; 1HNMR (400 MHz, DMSO-d6): δ 7.15 (d, J=8.7 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 6.29 (t, J=2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 2H), 3.78(t, J=8.7 Hz, 1H), 3.72(s, 6H), 3.62(s, 3H), 3.31(dd, J=13.5 and 8.4 Hz, 1H), 2.93(dd, J=13.5 and 6.9 Hz, 1H); MS (EI) m/z 317[M]+; Anal. (C18H20O5) C, H.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[F:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.CC(CCCC(CCCC(CCCC(CCC(O)=O)C)C)C)C>Cl[Cu]>[F:33][C:34]1[CH:35]=[C:36]([O:40][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Oc1cccc(F)c1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl[Cu]
Agent: CC(C)CCCC(C)CCCC(C)CCCC(C)CCC(=O)O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4cccc(F)c4)cn3)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) and 3-fluorophenol using a method similar to that described for D73 in Description 73 although 1 eq. CuCl and 0.25 eq. THMD were used. MS (ES): MH+ 535.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[N:10]1[CH:15]=[CH:14][N:13]=[C:12]2[C:16]([O:18][C:19](=[O:20])[C:11]=12)=[O:17].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH3:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:16]([C:12]1[C:11]([C:19]([OH:18])=[O:20])=[N:10][CH:15]=[CH:14][N:13]=1)=[O:17]
Reactant: Cc1cccc(Br)c1
Reactant: O=C1OC(=O)c2nccnc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2nccnc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The Grignard reagent from 8.5 g (50 mmol) 3-bromotoluene and 1.2 g magnesium in 50 ml ether was added dropwise at 0°-10° C. to a solution of 7.5 g (50 mmol) pyrazine-2,3-dicarboxylic acid anhydride in 100 ml THF and after completed addition, the solution that formed was stirred for 4 hours at room temperature. 500 ml cold, saturated NH4Cl solution was then added, it was extracted with ethyl acetate and the organic phase was dried, concentrated by evaporation and purified as in example 1a and 2a. Yield 4 g (32% of theoretical yield).
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:16]>C(O)(C([O-])=O)=O.C(O)(C([O-])=O)=O.O.O=[Ti].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6][OH:16])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCCN
Reactant: OCCO
Agent: O=[Ti]
Agent: O=C([O-])C(=O)O
Agent: [K+]
Solvent: O
Product: CCP(=O)(CCCN)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To 414 g (2 mol) of butyl ethyl(3-aminopropyl)phosphinate (produced as in Example 6) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyl oxalate followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuating to leave 374 g (96% of theory) of 2-hydroxyethyl ethyl(3-aminopropyl)phosphinate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH2:10]>CO>[N:1]1([CH:2]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:3][CH2:4][C:5]([OH:10])=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O
Reactant: c1ccc2[nH]ccc2c1
Solvent: CO
Product: O=C(O)CCC(n1ccc2ccccc21)n1ccc2ccccc21
Temperature: 35 °C
Reaction time: 24 h

Procedure:
282 mg of indole (2.4 mmol) were dissolved in 10 ml of CH3OH and 5 ml of H2O; 102 mg of semisuccinic aldehyde (1 mmol) and 240 mg of dysprosium triflate-(CF3SO3)3Dy-(0.393 mmol) were added. The resulting solution was stirred at 35° C. for 24 hours. At the end of that period the methanol was removed under vacuum and the residue was extracted with ethyl acetate (3×50 ml). The organic extracts were pooled, washed with a small amount of water, dried on anhydrous Na2SO4, filtered and concentrated to dryness. The end product was isolated and purified chromatographically on an SiO2 column, using a hexane:isopropyl alcohol gradient ranging from 9:1 to 8:2.
Reaction SMILES: N#N.[CH:3]1([C:6]2[S:7][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:11](O)=[O:12])[N:10]=2)[CH2:5][CH2:4]1.CN(C=O)C.C(Cl)(=O)C([Cl:28])=O>C1(C)C=CC=CC=1>[CH:3]1([C:6]2[S:7][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:11]([Cl:28])=[O:12])[N:10]=2)[CH2:5][CH2:4]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc(C2CC2)sc1-c1ccccc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc(C2CC2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-cyclopropyl-5-phenyl-thiazole-4-carboxylic acid (90 mg, 0.37 mmol) in toluene (2.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.11 mL, 1.25 mmol) and the resulting yellow solution was stirred at rt for 2 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-cyclopropyl-5-phenyl-thiazole-4-carbonyl chloride.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:29])[C:14]([C:26](O)=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:11][C:10]=2[F:30])[CH2:3]1.[CH3:31][C:32]1[CH:39]=[C:38]([O:40][C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:8][CH:6]1[NH:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:29])[C:14]([C:26]([NH:35][CH2:34][C:33]4[CH:36]=[CH:37][C:38]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:39][C:32]=4[CH3:31])=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:11][C:10]=2[F:30])[CH2:5]1
Reactant: Cc1cc(OC(F)(F)F)ccc1CN
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(CC(F)(F)F)c12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
212 mg (0.49 mmol) of 7-[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinoline-3-carboxylic acid (salt free compound of Example 50A) and 366 mg (0.98 mmol) of 2-methyl-4-trifluoromethoxybenzylamine (Example 69A) are dissolved together with 357 mg (0.69 mmol) of PyBOP and 30 mg (0.25 mmol) of 4-dimethylaminopyridine in 4 ml of DMF and stirred for 12 h at room temperature. The reaction mixture is then purified by preparative HPLC (Method 7). A solid is obtained. Yield: 170 mg (56% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=2[N:9]=1.[C:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)#[CH:27]>>[F:21][C:17]1([F:20])[CH2:18][CH2:19][CH:14]([CH2:13][N:12]2[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:27]#[C:26][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:15][CH2:16]1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: FC1(F)CCC(Cn2c(-c3ccccc3Br)nc3ccccc32)CC1
Product: N#Cc1ccc(C#Cc2ccccc2-c2nc3ccccc3n2CC2CCC(F)(F)CC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-(4,4-difluoro-cyclohexylmethyl)-1H-benzoimidazole and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). Brown solid (38%). MS (Turbo Spray): m/z=452.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:11]/[C@@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:44]1(=[O:48])[CH2:47][CH2:46][CH2:45]1.[Cl-].[NH4+]>O1CCCC1>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([C:44]3([OH:48])[CH2:47][CH2:46][CH2:45]3)=[C:7]([O:8][CH3:9])[N:6]=2)=[CH:11][CH:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:15](=[O:28])[CH2:14][CH2:13]2)=[CH:34][CH:33]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CCC2C=C(c2ccc(C(C)(C)C)cc2)c2ccc(C3(O)CCC3)c(OC)n2)c(OC)c1
Reaction time: 0.5 h

Procedure:
(5R)-5-[(E)-2-(5-Bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (100 mg) was dissolved in tetrahydrofuran (5 mL), and n-butyllithium was added at −78° C. After stirring for 30 minutes, cyclobutanone was added dropwise. The mixture was stirred for further 30 minutes and then an ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 5-{2-(4-tert-butylphenyl)-2-[5-(1-hydroxycyclobutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (EZ mixture) (35 mg).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:33]>CO>[NH3:7].[NH2:33][CH2:28][C@H:26]([OH:27])[CH2:25][O:24][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:14]2[N:13]=[C:12]([C:10]3[CH:9]=[C:8]([O:31][CH3:32])[N:7]=[C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:11]=3)[O:16][N:15]=2)=[CH:18][C:19]=1[CH2:29][CH3:30]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H]1CO1
Agent: N
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H](O)CN

Procedure:
A solution of (S)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-3-(3-ethyl-5-methyl-4-(oxiran-2-ylmethoxy)phenyl)-1,2,4-oxadiazole (350 mg, 0.804 mmol) in 7 N NH3 in methanol (15 mL) is stirred at 45° C. for 18 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with DCM:7 N NH3 in methanol 94:6 to give (S)-1-amino-3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propan-2-ol (256 mg) as a pale yellow solid; LC-MS: tR=0.83 min, [M+H]+=453.22.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH:15]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][CH:15]([N:18]([CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[CH3:17]
Reactant: CC(C)NCCNC(C)C
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCNC(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Acetaminobenzene sulfonyl chloride (23.3 g, 0.1 mole) as a slurry in 400 ml methylene chloride was added to N,N'-diisopropyl ethylene diamine (14.46 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (600 ml). The reaction was stirred overnight at room temperature. The reaction was washed with water, insoluble by-product filtered off, and the filtrate stripped to a brown gum. After filtration through silica gel in 20% MeOH/EtOAc the crude crystalline product was recrystallized from isopropanol to provide the title product as the hydrochloride salt (3.00 g, m.r. 176°-178° C.).
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:29])=[CH:22][CH:23]=4)[C:18](=O)[C:17]=3[CH:16]=2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.[Pd]>[ClH:1].[ClH:1].[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[O:29])=[CH:22][CH:23]=4)[CH2:18][C:17]=3[CH:16]=2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(OCCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN3CCCCC3)ccc1-2
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C(OCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)OCCCN3CCCCC3)ccc1-2

Procedure:
A solution of 20.0 g (0.04 mole) of bis(3-piperidinopropyl)-9-oxofluorene-2,7-dicarboxylate dihydrochloride in water to make a total volume of 240 ml is hydrogenated over 8.0 g of 10% palladium on charcoal for 2 days at 53° C. on a Parr hydrogenation apparatus. The mixture is decanted from the catalyst, filtered through filter aid, treated with charcoal and refiltered. The solution is made basic to phenolphthalein with 20% sodium hydroxide and is extracted three times with CHCl3. The combined extracts are washed twice with water, dried over anhydrous sodium sulfate and filtered. The filtrate is made acidic to Congo Red with ethereal HCl. Most of the solvent is removed on a steam bath under vacuum, and the resulting solid is recrystallized from methanol-ether and from absolute ethanol and vacuum dried to give bis(3-piperidinopropyl)fluorene-2,7-dicarboxylate dihydrochloride.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].[CH3:12][C:13]1[C:14]([C@H:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:20]2[CH2:32][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35](F)[CH:34]=2)=[N:15][CH:16]=[CH:17][CH:18]=1>CN(C=O)C>[CH3:31][C:30]1[C:25]([C@H:21]2[CH2:22][CH2:23][CH2:24][C@@H:19]([C:14]3[C:13]([CH3:12])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:20]2[CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]#[N:38])=[C:39]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])[CH:40]=2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccc(C#N)c(F)c1
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(CN2[C@@H](c3ncccc3C)CCC[C@H]2c2ncccc2C)ccc1C#N
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of potassium tert-butoxide (0.140 g, 1.25 mmol) in dry DMF (5 mL) was added acetone oxime (0.0877 g, 1.20 mmol), and the mixture was stirred for 30 min. A solution of 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-fluoro-benzonitrile (0.400 g, 1.00 mmol) in dry DMF (5 mL) was then added, and the mixture was stirred overnight. The solvent was then removed by evaporation under vacuum, and saturated aqueous NaHCO3 (10 mL) was added. The mixture was extracted with EtOAc (3×30 mL), and the extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (1000:25:1 CH2Cl2/CH3OH/NH4OH), affording 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-isopropylideneaminooxy-benzonitrile as a pale yellow solid (0.311 g, 69%). 1H NMR (CDCl3) δ 1.65-1.75 (m, 3H), 2.06 (s, 3H), 2.07 (s, 3H), 2.09-2.14 (m, 1H), 2.20-2.40 (m, 2H), 2.45 (s, 6H), 3.58 (s, 2H), 4.19 (s, 1H), 4.23 (s, 1H), 6.14 (d, 1H, J=7.8 Hz), 6.68 (s, 1H), 6.91-6.96 (m, 3H), 7.22 (d, 2H, J=7.2 Hz), 8.35 (d, 2H, J=3.9 Hz).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:6]([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:7][C:8](=[N:11][OH:12])[CH:9]=O)[CH3:5]>C(Cl)(Cl)Cl.CO>[CH2:4]([C:6]([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:7][C:8](=[N:11][OH:12])[CH:9]=[N:2][OH:3])[CH3:5]
Reactant: NO
Reactant: CCC(=CC(C=O)=NO)C(C)[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(=CC(C=NO)=NO)C(C)[N+](=O)[O-]
Temperature: 25 °C
Yield: 60.5 %

Procedure:
Hydroxylamine hydrochloride (69.5 mg) was added to a solution of 4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) in a mixture of chloroform (3 ml) and methanol (2 ml) with stirring at room temperature. The resulting mixture was stirred at the same temperature overnight and evaporated to dryness. The residue was washed successively with water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was distilled under reduced pressure to give a residue which was purified by preparative thin layer chromatography [solvent: methanol-chloroform (10:90)] to give 4-ethyl-2-hydroxyimino-5- nitro-3-hexenaldehyde oxime (65 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][N:25]=2)[C:20]([C:27](=[O:31])[C:28](Cl)=[O:29])=[CH:19]1>C1COCC1>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:28](=[O:29])[C:27]([C:20]1[C:21]2[C:26](=[N:25][CH:24]=[CH:23][CH:22]=2)[N:18]([CH2:17][C:16]2[CH:32]=[CH:33][CH:34]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH:19]=1)=[O:31]
Reactant: COc1cccc(Cn2cc(C(=O)C(=O)Cl)c3cccnc32)c1
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(Cn2cc(C(=O)C(=O)Nc3c(Cl)cncc3Cl)c3cccnc32)c1
Reaction time: 1 h

Procedure:
To a suspension of 2 g of sodium hydride in 20 mL of THF, 2.4 g of 4-amino-3,5-dichloropyridine (15 mmoles) in 30 mL of THF are added dropwise at −5° C. The mixture is then kept for one hour at 20° C. with stirring. Subsequently, the previously prepared suspension of 1-(3-methoxybenzyl)-7-azaindole-3-yl-glyoxylic acid chloride is added dropwise at about 0° C. Finally, the reaction mixture is refluxed for 4 hours, after which the solvent is removed under vacuum. The residue is stirred with 50 mL of ethyl acetate and 50 mL of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off under vacuum and the residue recrystallized from isopropanol.