Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1([CH2:16][CH2:17][CH3:18])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[NH3:19]>CO.[Ni]>[CH2:8]1[C:3]2([CH2:16][CH2:17][CH2:18][NH:19][CH2:1]2)[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7]1
Reactant: CCCC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Temperature: 110 °C

Procedure:
Tert-butyl 4-formyl-4-propylpiperidinecarboxylate (30 g) was dissolved in a saturated solution of ammonia in methanol, and 15 g of Raney Ni was added. The reaction mixture was heated to 110° C. at 80 atmospheres pressure in a 2 L high-pressure autoclave. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give residue which was purified by column chromatography to afford tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([CH3:9])[CH:5]=[C:4](Cl)[N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: Cc1cc(Cl)nc(C)[n+]1[O-]
Reactant: C1CCNCC1
Product: Cc1cc(N2CCCCC2)nc(C)[n+]1[O-]

Procedure:
100 ml of piperidine are introduced into a 250 ml three-necked flask fitted with a thermometer, a condenser and a magnetic stirrer and 13.5 g (8.51×10-2 mol) of 2,4-dimethyl-6-chloropyrimidine 3-oxide are then added, in solid portions, in a manner such that exothermic heat does not develop beyond 60° C. The reaction mixture is then allowed to return to ambient temperature; the piperidinium hydrochloride is then removed from the mixture by filtration and the filtrate is evaporated to dryness. The crude oil obtained crystallises rapidly at ambient temperature. The crystalline mass is dissolved in a minimum of ethanol and ethyl ether is then added cold until precipitation occurs. The mixture is stirred for half an hour and the precipitate is then filtered off and drained. A final filtration through silica gel using the dichloromethane/methanol (90/10) eluent system allows white crystals to be obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10](OC)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1nc(SC)ncc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(CO)n1
Reaction time: 0.03 h

Procedure:
To a cold (−10° C.˜0° C.) THF (19.00 mL) solution of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (Step A, 1 g, 3.80 mmol) was added diisobutylaluminum hydride (1M, 9.50 mL, 9.50 mmol) while internal temperature was below 0° C. An aliquot taken immediately after addition indicated completion of reaction. The crude mixture was quenched with NH4Cl (aq.). Volatiles were removed under reduced pressure. The resulting pot residue was worked up with brine, extracted with EtOAc, dried (Na2SO4), filtered and evaporated to afford a dark mixture. The dark residue was purified by preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 80% organic in 10 min, then to 100% in 2 min). Related fractions were pooled and evaporated in vacuo to afford an aqueous mixture. The resulting mixture was extracted with EtOAc and washed with aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to afford a brown oil. After further drying under reduced pressure, this oil solidified to a crystalline solid. LCMS calc.=235.94; found=236.88.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:28])=[C:6]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])[C:10]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:9]2)[CH:7]=1.[C:29](Br)(=[O:32])[CH2:30][CH3:31]>CN(C1C=CN=CC=1)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:11]2[C:10]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:9][N:8]([C:6]3[CH:7]=[C:2]([NH:1][C:29](=[O:32])[CH2:30][CH3:31])[CH:3]=[CH:4][C:5]=3[Cl:28])[C:12]=2[C:13]#[N:14])=[C:17]([F:23])[CH:18]=1
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Reactant: CCC(=O)Br
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Yield: 73 %

Procedure:
The acylation of 1-(5-amino-2-chlorophenyl)-4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1H-pyrazole-5-carbonitrile (from Step G) with propionyl bromide in the presence of DMAP followed the procedure of Example 1, Step J. Flash chromatography of the crude product on silica gel (gradient elution with 5:1 to 3:1 hexane-EtOAc) afforded a 73% yield of the title compound as a tacky oil; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 517, 519 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.3 Hz, 3H), 1.22 (t, J=7.6 Hz, 3H), 1.32 (m, 2H), 1.54 (m, 2H, partially obscured by H2O peak), 2.38 (q, J=7.6 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 3.92 (s, 2H), 7.02 (dd, J≈8, 8.5 Hz, 1 H), 7.22-7.26 (m, 2H), 7.4-7.5 (m, 2H), 7.90 (d, J=2.2 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[N:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12](O)=[O:13])[CH3:8].C[N:21](C)C=O>C(Cl)Cl>[CH2:7]([O:9][C:10]1[N:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([NH2:21])=[O:13])[CH3:8]
Reactant: CN(C)C=O
Reactant: CCOc1ncc(I)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOc1ncc(I)cc1C(N)=O
Temperature: 25 °C
Yield: 95 %

Procedure:
Oxalyl chloride (6.60 ml, 75.1 mmol) was added to a solution of 2-ethoxy-5-iodonicotinic acid (prepared according to the procedure in WO0127112, 20.0 g, 68.3 mmol) in DCM (400 ml) and N,N-dimethylformamide (0.1 ml) at 0° C. The solution was warmed to room temperature over 18 h and then concentrated in vacuo. The resultant orange oil was dissolved in THF (200 ml) and cooled to 0° C. NH3 (410 ml of a 0.5 M soln. in dioxane, 205 mmol) was added and the mixture was warmed to room temperature over 4 h. The reaction mixture was concentrated in vacuo and triturated with water (150 ml). The solid was filtered and dried to afford the title compound as a beige solid (18.9 g, 64.9 mmol, 95%); m.p. 176-179° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]2=[N:9][CH:10]=1.CC[C:25]([O-:27])=[O:26]>O.C(O)C>[F:22][C:4]([F:21])([F:3])[C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:25]([OH:27])=[O:26])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]2=[N:9][CH:10]=1
Reactant: FC(F)(F)c1cnc2c(ccn2Cc2ccncc2)c1
Reactant: CCC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1ccncc1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A solution of 0.39 g (6.87 mmol) of potassium hydroxide in 2 mL of water is added to a solution, in 30 mL of ethanol, of 0.8 g (2.29 mmol) of 5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate, obtained in Stage 9.1. The mixture is stirred for four hours under reflux. After this time the reaction mixture is concentrated at reduced pressure, and is then taken up in 40 mL of water. The reaction mixture is acidified to pH 5 by successive additions of concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and then dried at reduced pressure. In this way we isolate 0.54 g of the expected product, in the form of a white powder, which is used as it is in the next stage.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=1.C(Cl)Cl>ClC1C=CC=CC=1Cl>[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([C:23]2[O:22][C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:25][CH:24]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: c1ccc(-c2ccco2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Temperature: 80 °C

Procedure:
Phosphorous pentoxide (2.02 g, 14.20 mmol) suspended in 1,2-dichlorobenzene (60 mL) was added to a mixture of 2-phenyl-furan (23) (500 mg, 2.84 mmol) and 3-bromophenylacetic acid (24) (1.34 g, 6.25 mmol). The reaction mixture was heated to 80° C. for 2 hours and then cooled to ambient temperature. DCM was added, the organic layer washed with water and partially reduced in vacuo. The crude product was purified by Flash Master Jones Chromatography using a 50 g silica cartridge and first eluting with heptane to remove excess 1,2-dichlorobenzene, then 5-10% EtOAc in heptane to give the title compound. Yield: 278 mg, 38%; LC-MS tr 1.73 min; HPLC Purity: 100%; MS (ES+) m/z 341, 343 (M+H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:30]=2)[CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 8.09 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.65 (s, 1H), 5.50 (s, 2H), 2.68 (s, 3H); MS (ES) m/z 519 (M+1).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][S:25]([CH:22]3[CH2:24][CH2:23]3)(=[O:27])=[O:26])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,5-diamine (200 mg, 0.73 mmol) was dissolved in 2 mL pyridine and cyclopropane sulfonylchloride (102 mg, 0.73 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched by addition of 50 mL water and acetic acid until pH 5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0→50:50 gradient). The title compound was obtained as a brown solid (160 mg, 58%), MS: m/e=380.4 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[C:18]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[N:24][CH:25]=2)=[CH:17][CH:16]=[C:15]([CH:26]2[CH2:28][CH2:27]2)[N:14]=1)=[O:12].[OH-].[Na+]>CO.O>[CH:26]1([C:15]2[N:14]=[C:13]([C:11]([NH:10][C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:29])=[O:2])=[O:12])[C:18]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[N:22][CH:21]=3)=[CH:17][CH:16]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1

Procedure:
To stirred suspension of 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid methyl ester (330 mg, 0.84 mmol) in MeOH (5 ml) was added a solution of NaOH (84.5 mg, 2.1 mmol) in water (2 ml) at 0-5° C. After the addition the reaction mixture was stirred at rt for 8 hrs. The solvent was removed in vacuo, the residue was dissolved in water (7 ml), and was washed with EtOAc (2×10 ml). The aqueous layer was then acidified with 1N HCl (pH˜2), and concentrated to obtain the title compound (containing NaCl) as a yellowish sticky solid which was directly used as such for the next step without any further purification.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)[CH2:10][CH2:9]1)=O)(C)C.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][C:35]([CH2:37][N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]3)=[CH:34][CH:33]=2)[CH:29]=[CH:30][CH:31]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:51][C@@H:40]1[NH:41][CH2:42][CH2:43][N:38]([CH2:37][C:35]2[S:36][C:32]([C:28]3[CH:27]=[C:26]([CH2:25][NH:24][C:18](=[O:20])[C:17]4[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:16]=4)[CH:31]=[CH:30][CH:29]=3)=[CH:33][CH:34]=2)[CH2:39]1
Reactant: C[C@H]1CN(Cc2ccc(-c3cccc(CN)c3)s2)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(Cc2ccc(-c3cccc(CNC(=O)c4cccc(CC5CCNCC5)c4)c3)s2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (319 mg, 1.0 mmol) in CHCl3 (5.0 mL) was added 1,1-dimethylethyl (2S)-4-({5-[3-(aminomethyl)phenyl]-2-thienyl)methyl)-2-methyl-1-piperazinecarboxylate (401 mg, 1.0 mmol), TEA (0.26 ml, 2 mmol), EDC (288 mg, 1.5 mmol) and HOBt (150 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 2 h, followed by addition of 1 mL of saturated Na2CO3. The organic layer was dried over Na2SO4, and filtered. The filtrate was mixed with 1 mL of TFA, and stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (261 mg, 52%). LC/MS: m/z, 502 (M+H), 1.31 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC1CCCNC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: OC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
943 mg of 3-hydroxypiperidine was dissolved in 15 mL of toluene, to which, under ice cooling, 1.13 mL of benzaldehyde, 2.97 g of sodium triacetoxyborohydride and 0.3 mL of acetic acid were sequentially added, and stirred at room temperature for 24 hours. To the reaction mixture, saturated sodium bicarbonate was added, extracted with ethyl acetate, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform to chloroform:methanol-ammonia=60:1) to obtain 866.3 mg (49%) of 1-benzyl-3-hydroxypiperidine crude product as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH:6]/[C:7](=[CH:13]\[C:14]([O:16]CC)=O)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=[N:2]1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:16]=[C:14]1[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][C:4]2[CH:5]=[N:1][NH:2][C:3]1=2
Reactant: CCOC(=O)/C=C(\Nc1cn[nH]c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cc(=O)c2[nH]ncc2[nH]1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
Diethyl 2-(pyrazol-4-ylamino)fumarate (7.74 g, 30 mmol) was added to boiling Dowtherm A (250 ml). The solution was heated under reflux for 10 min, and then allowed to cool to room temperature. 60°-80° petrol (250 ml) added and the solid was collected and washed well with petrol, to give the title compound as pale yellow needles (5.77 g, 99%), m.p. 287°-292° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:15])[CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[N:30][C:31]([Cl:37])=[CH:32][CH:33]=2)[N:28]=1.Cl>CN(C)C=O.O>[Cl:37][C:31]1[N:30]=[C:29]2[C:34]([CH:35]=[CH:36][C:27]([N:18]3[C:19](=[O:26])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]3[CH:8]([C:7](=[O:14])[CH2:6][CH2:5][C:4]([CH3:3])=[CH2:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:28]2)=[CH:33][CH:32]=1
Reactant: C=C(C)CCC(=O)CC(=O)OCC
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CCC(=O)C(C(=O)OCC)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1.7 g of an oily suspension (50% by weight) of sodium hydride are added to 100 cm3 of anhydrous dimethylformamide, under an argon atmosphere, at a temperature of about 10° C. 9.8 g of ethyl 6-methyl-3-oxo-6-heptenoate in 25 cm3 of anhydrous dimethylformamide are subsequently added. The suspension is stirred for 30 minutes and the temperature is allowed to return to about 20° C., followed by the addition of 11.6 g of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone. The reaction mixture is stirred for 4 hours at a temperature of about 20° C. and is then poured into 250 cm3 of water. The aqueous phase, which is acidified by the addition of 25 cm3 of aqueous 1N hydrochloric acid solution, is extracted twice with 200 cm3 of dichloromethane. The organic phases are combined and washed twice with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The oily residue is purified by chromatography on silica [eluent:ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After crystallization in diisopropyl ether, 9.4 g of ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxo-6-heptenoate (mixture of A and B forms) are thus obtained, melting at 125° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:12].[CH3:13][C:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:13][C:14]1([C:20]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[S:12][C:20]([C:14]2([CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:21])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: Nc1c(S)ccc2ccccc12
Solvent: c1ccncc1
Product: CC1(C(=O)Nc2c(SC(=O)C3(C)CCCCC3)ccc3ccccc23)CCCCC1
Temperature: 60 °C

Procedure:
To a solution of 1-amino-naphthalene-2-thiol in pyridine are added two mol equivalents of 1-methyl-cyclohexanecarbonyl chloride at room temperature. After completion of the addition, the reaction mixture is heated to 60° C. for 2 hours. The pyridine is then removed under reduced pressure, water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with sat. NaHCO3-solution, diluted hydrochloric acid and brine, dried (Na2SO4) and concentrated to obtain crude 1-methyl-cyclohexanecarbothioic acid S-{1-[(1-methyl-cyclohexanecarbonyl)-amino]-naphthalen-2-yl}ester.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]([CH3:13])[C:8]([O:10]CC)=[O:9])[CH3:5])[CH3:2].[OH-].[K+:15].O.C(O)C>>[CH2:1]([O:3][CH:4]([O:6][CH:7]([CH3:13])[C:8]([O-:10])=[O:9])[CH3:5])[CH3:2].[K+:15]
Reactant: CCOC(=O)C(C)OC(C)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(C)OC(C)C(=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
To a 250 mL flask containing 38.0 g (0.20 moles) ethyl 2-[(1'-ethoxy)ethoxy]propanoate at 23° C. is added a solution of 14.8 g (0.264 moles) KOH, 30.0 g (1.667 moles) water and 10.0 g (0.217 moles) ethanol over a 30 minute period. Maintaining ±23° C., the solution is stirred for one hour, then extracted with 20 g hexane. The aqueous phase is then stripped of all solvent under vacuum. A constant weight of 43.7 g potassium 2-[(1'-ethoxy)ethoxy]propanoate is obtained as a yellowish viscous liquid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:9])=[CH:5][CH2:6][CH2:7][OH:8].Br[CH2:11][CH2:12][CH2:13][C:14]1([O:19][CH2:18][CH2:17][O:16]1)[CH3:15].O>CN(C)C=O>[CH2:17]1[CH2:18][O:19][C:14]([CH2:13][CH2:12][CH2:11][O:8][CH2:7][CH2:6][CH:5]=[C:4]([CH3:9])[CH3:3])([CH3:15])[O:16]1
Reactant: CC(C)=CCCO
Reactant: CC1(CCCBr)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCOCCCC1(C)OCCO1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
14 g of sodium hydride in a 50% suspension in oil were added to a solution of 28 g of 4-methyl-3-pentenol [Julia et al, Bull. Soc. Chim., (1960), p. 1072] in 250 ml of dimethylformamide and after stirring the mixture for 1 hour, 66 g of 5-bromo-2,2-ethylenedioxy-pentane were added thereto while keeping the temperature below 35° C. The mixture was stirred at room temperature for 17 hours and the reaction mixture was then poured into water. The mixture was extracted with petroleum ether (b.p.= 40°-75° C.) and the organic phase was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was rectified to obtain 20 g of 2,2-ethylenedioxy-10-methyl-6-oxa-9-undecene in the form of a colorless liquid with a boiling point of 75° C. at 0.05 mm Hg.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9]O.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:11][CH2:9][CH2:8][CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2
Reactant: OCCC1CC2CCC1C2
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: BrCCC1CC2CCC1C2
Yield: 95.3 %

Procedure:
2-Bicylco[2.2.1]hept-2-yl-ethanol (13.0 g, 93 mmol) was dissolved in acetonitrile (200 mL) and treated with dibromotriphenylphosphorane (47.0 g, 0.11 mol). After 1.5 hours the mixture was quenched with water (10 mL), diluted with diethyl ether (400 mL), and washed with water (2×400 mL). The organic phase was dried (MgSO4) and concentrated to yield an oil. The product was passed through a pad of silica gel to yield 2-(2-bromo-ethyl)-bicyclo[2.2.1]heptane as a colorless oil (18 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 3.37 (t, 7.4 Hz, 2 H), 2.22 (m, 1 H), 1.97 (m, 1 H), 1.86 (m, 1 H), 1.7-1.4 (m, 5 H), 1.3-0.9 (m, 5 H); MS (FAB) m/z 203 (MH+).