Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:24][C:25]=2[O:27][CH:28]([CH3:30])[CH3:29])[N:20]=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56].[I-].[Na+]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34][N:60]3[CH2:61][CH2:62][N:57]([CH:55]=[O:56])[CH2:58][CH2:59]3)=[CH:24][C:25]=2[O:27][CH:28]([CH3:29])[CH3:30])[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Reactant: O=CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C=O)CC4)cc(OC(C)C)c23)c2c1OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (0.320 g, as a 1:1.3 wt.:wt. mixture with triphenylphosphine) and N-formyl piperazine (0.69 ml) was dissolved in 2-methoxyethanol (7 ml), then sodium iodide (0.040 g) was added and the reaction mixture was then heated at 110° C. with stirring for 24 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (70 ml) and washed with water:brine (1:1) then water then brine and dried over magnesium sulfate before filtration and evaporation of solvents under reduced pressure. The residues so resulting were then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained the title compound (0.086 g) as a white foam; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.03 (quin, 2H), 2.47 (dt, 4H), 2.58 (t, 2H), 3.40 (t, 2H), 3.45 (s, 3H), 3.58 (t, 2H), 4.16 (t, 2H), 4.35 (s, 2H), 4.82 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.83 (d, 1H), 7.06 (s, 1H), 8.03 (s, 1H), 8.51 (s, 1H), 9.41 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:23]([C:24]2[CH:29]=[CH:28][C:27](OC)=[C:26]([C:32](=[O:44])[NH:33][C:34]3([C:38]4[N:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH2:37][O:36][CH2:35]3)[CH:25]=2)=[CH:22][C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2].N1C=CC=CC=1.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>CN(C1C=CN=CC=1)C.O>[CH2:1]([N:3]([C:4]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:32](=[O:44])[NH:33][C:34]3([C:38]4[N:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH2:37][O:36][CH2:35]3)[CH:25]=2)=[CH:22][C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[S:52]([CH3:51])(=[O:54])=[O:53])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNc1cc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)COC2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC2(c3ncccn3)COC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(ethylamino)-2-(4-fluorophenyl)-5-(4-methoxy-3-((3-(pyrimidin-2-yl)oxetan-3-yl)carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (90 mg, 0.151 mmol), pyridine (5.0 mL), DMAP (18.46 mg, 0.151 mmol) and methanesulfonyl chloride (0.018 mL, 0.227 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (20 ml×2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by prep HPLC.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[C@H:15](O)[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1.[O:23]=[O:24]>>[O:23]([C@:4]12[CH2:3][C@@H:2]([OH:1])[CH2:19][CH2:18][C@:17]1([CH3:20])[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]3)[CH:6]=[CH:5]2)[OH:24]
Reactant: O=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@@]4(OO)C[C@@H](O)CC[C@]34C)[C@@H]1CCC2=O

Procedure:
3β-Hydroxyandrost-5-en-17-one (DHEA) 1 reacts with singlet oxygen to yield 5α-hydroperoxy-3β-hydroxy-androst-6-en-17-one 2. This hydroperoxide undergoes a rearrangement when in chloroform solution to yield 7α-hydroperoxy-3β-hydroxyandrost-5-en-17-one, 3. Treatment of the hydroperoxide with zinc and acetic acid yields 3β,7α-dihydroxy-androst-5-en-17-one, 4. ##STR35##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([N:21]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]3[N:14]([C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.Cl[C:47]([O:49][CH3:50])=[O:48]>C1COCC1>[C:19]([C:16]1[N:14]2[N:15]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:47](=[O:48])[O:49][CH3:50])[CH:3]=3)[CH:11]=[C:12]([N:21]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]2=[N:18][CH:17]=1)#[N:20]
Reactant: COC(=O)Cl
Reactant: COc1ccc(CN(c2ccccn2)c2cc(Nc3ccc(F)c(N)c3)nn3c(C#N)cnc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(Nc2cc(N(Cc3ccc(OC)cc3)c3ccccn3)c3ncc(C#N)n3n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.4 %

Procedure:
A solution of 8B (82 mg, 0.17 mmol) in THF (3 mL) was treated with DIEA (0.039 mL, 0.22 mmol), followed by methyl chloroformate (0.048 mL, 0.62 mmol). The resulting solution was stirred at room temperature for 12 hours and then concentrated to dryness. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, DCM to 20% ethyl acetate/DCM, 24 g column, 40 min. gradient) to afford 8C (15 mg, 16.3%). HPLC: Rt=3.98 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=539.2 [M+H]+.
Reaction SMILES: C1([SH:7])C=CC=CC=1.F[C:9]1[CH:10]=[C:11]([C:16]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:17])[CH:12]=[C:13]([F:15])[CH:14]=1.[CH:23]([Mg]Br)([CH3:25])[CH3:24].C([Mg]Br)=C>C1COCC1>[F:15][C:13]1[CH:12]=[C:11]([C:16]([OH:17])([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:23]([CH3:25])[CH3:24])[CH:10]=[C:9]([SH:7])[CH:14]=1
Reactant: CC(C)[Mg]Br
Reactant: Sc1ccccc1
Reactant: O=C(c1cc(F)cc(F)c1)c1nccs1
Agent: C=C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)(c1cc(F)cc(S)c1)c1nccs1

Procedure:
Following the procedure described for Thiophenol 2, Step 3 and Thiophenol 5, Steps 2 and 3 but substituting the ketone from Thiophenol 5, Step 1 for (3,5-difluorophenyl)(thiazol-2-yl)-methanone and isopropylmagnesium bromide (Aldrich) in THF for vinylmagnesium bromide as starting material the title compound was obtained.
Reaction SMILES: C1(C([N:6]2[C:14]3[CH:13]=[C:12]([N:15]([C:21]([CH3:28])([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])[C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:11]=[CH:10][C:9]=3[CH:8]=[CH:7]2)=O)CC1.C(=O)([O-])[O-].[K+].[K+].CO>O>[NH:6]1[C:14]2[CH:13]=[C:12]([N:15]([C:21]([CH3:28])([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])[C:16]([CH:18]3[CH2:19][CH2:20]3)=[O:17])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1
Reactant: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2c(ccn2C(=O)C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CC(C)(C)N(C(=O)C1CC1)c1cc2[nH]ccc2cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-[1-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]-N-(2,4,4-trimethylpentan-2-yl)cyclopropanecarboxamide (65 mg, 0.16 mmol), potassium carbonate, methanol and water was stirred at room temperature for 20 minutes. Methanol was removed under vacuum. The residue was stirred in water for 30 minutes. The precipitated solid was filtered and dried to 47 mg (90%) N-(1H-pyrrolo[3,2-c]pyridin-6-yl)-N-(2,4,4-trimethylpentan-2-yl)cyclopropane carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:25]5[NH:24][C:32]6[C:27]([CH:26]=5)=[CH:28][CH:29]=[CH:30][CH:31]=6)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc2ccccc2[nH]1
Yield: 69.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 1H-indole-2-carboxylic acid (93 mg, 0.581 mmol), oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (3 mL) as starting materials and in the same manner as in Example 412, the title compound (153 mg, 70%) was obtained as a white powder.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].C(Cl)Cl.CCCCCC.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.OS(O)(=O)=O>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.17 k9 (12.3 mole) of (±)-trans-2-phenylcyclohexanol, 1475 mL (18.43 mole) of chloroacetyl chloride, 6 g (0.049 mole) of 4-dimethylaminopyridine, and 5.5 L of methylene chloride was heated at reflux. After 8 hours, thin layer chromatography analysis (4:1 hexane-ethyl acetate: Spray 5% NH4MoO4 in 10% aqueous H2SO4) indicated complete reaction. The reaction mixture was allowed to cool to room temperature and was stirred with 2×4 L=8 L of saturated NaHC03. The organic layer was dried (Na2SO4) evaporated in vacuo on a rotary evaporator, and finally at 0.5 mmHg to afford 3.21 kg of crude (±)-trans-2-phenylcyclohexyl chloroacetate. Distillation of the tan liquid afforded 2.76 kg (88%) of the desired product as a colorless liquid, (b.p. 125-133°/0.3-0.5 mmHg). The chloroacetylation of other lots of (±)-trans-2-phenylcyclohexanol was accomplished in ← 95%. The particular lot of (±) alcohol used in this example was only about 91% pure.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20]C)=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O>CO>[C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Yield: 77.6 %

Procedure:
Methyl 2-phenyl-4-quinolone-6-carboxylate (3.8 grams) obtained in Example 1 is refluxed for three hours in a mixture of 100 ml of methanol, 3 grams of sodium hydroxide and 15 ml of water. The mixture is evaporated to dryness in vacuo, 100 ml of water is added to the residue, filtered, acidified with 10% hydrochloric acid solution, and the crystals which separate out therefrom are collected by filtration. These are recrystallized from dimethyl formamide to give 2.8 grams of 2-phenyl-4-quinolone-6-carboxylic acid, colorless powder, melting at above 300° C.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]1[CH:21]=[C:22]2[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:26][C:23]2=[N:24][CH:25]=1.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:26]2[C:23]3=[N:24][CH:25]=[C:20]([F:19])[CH:21]=[C:22]3[CH:28]=[C:27]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1cc2cc(F)cnc2[nH]1
Reactant: OCc1ccncc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)cnc2n1Cc1ccncc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
9.18 g (36.02 mmol) of 1,1′-(azodicarbonyl)dipiperidine are added, in a quarter of an hour, to a solution, stirred at 20° C., of 5 g (24.02 mmol) of ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Example 21.3), 3.97 g (36.02 mmol) of (pyridin-4-yl)methanol and 7.5 g (36.02 mmol) of tributylphosphine in 150 ml of toluene. The reaction mixture is stirred at 20° C. for 16 hours, filtered over a celite buffer, concentrated under reduced pressure and then taken up in 100 ml of dichloromethane. The organic solution is washed twice with 50 ml of a 5% aqueous solution of potassium carbonate and then once with 50 ml of water, dried over sodium sulphate and concentrated under reduced pressure. The product obtained is chromatographed on a silica column, elution being carried out with a mixture of heptane and ethyl acetate. 4.5 g of the expected ester are thus isolated.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Cl[C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:19]1[N:18]=[C:17]([NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(Cl)cc3nccnc23)C1

Procedure:
A solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (100 mg, 0.5 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (100 mg, 0.5 mmol) and DIPEA (77 mg, 0.6 mmol) in THF (5 mL) was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was treated with ethyl acetate, with brine, and concentrated to give the crude title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[S:14]([NH2:17])(=[O:16])=[O:15])[CH2:3][CH2:2]1.[CH:18]([O-])([O-])OCC>>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=3[S:14](=[O:16])(=[O:15])[N:17]=[CH:18]2)[CH2:3][CH2:2]1
Reactant: CCOC([O-])[O-]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NC1CC1
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=CN2C1CC1
Temperature: 130 °C

Procedure:
In a round-bottom flask, a mixture of 2-cyclopropylamino-5-nitrobenzenesulphonamide (5 g), originating from the Step above, and ethyl orthoformate (50 mL) is heated in the open state at 130° C. for 3 hours. The suspension obtained is cooled on an ice bath and the insoluble material is collected by filtration, washed with ether and dried.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]#[CH:9])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:10]([O:12]CC)C.C([Li])CCC.C=O>CCCCCC.O>[CH2:1]([O:6][CH2:7][C:8]#[C:9][CH2:10][OH:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOCC
Reactant: C#CCOCCCCC
Agent: C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCCCCOCC#CCO
Temperature: -78 °C

Procedure:
To a 500 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 10 grams (g) of 3-(pentyloxy)prop-1-yne (0.72 mmol), and 140 mL of dry ethyl ether. The reaction mixture was cooled to −78° C. with stirring followed by the dropwise addition of 37.5 mls (60 mmole) of 1.6M n-Butyl lithium solution in hexane. The temperature was adjusted to 0° C. and 5.4 g (180 mmole) of solid paraformaldehyde was added. The mixture was then stirred at ambient temperature overnight. Ether and water was added to the mixture and the ether layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum on a rotary evaporator. Isolated 9.44 g of a colorless liquid which was consistent with the desired structure upon analysis by 300 MHz 1H NMR.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7]Br.C([O-])(O)=[O:14].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7][OH:14]
Reactant: O=C([O-])O
Reactant: BrCc1c(Br)oc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1c(Br)oc2ccccc12
Temperature: 25 °C

Procedure:
2-bromo-3-bromomethyl benzofuran prepared from Step A (7.67 g, 26.45 mmol) was immediately dissolved in dioxane (30 mL), followed by a solution of NaHCO3 (2.67 g, 1.2 eq.) in water (30 mL). The mixture was refluxed for 1 h with vigorous stirring, cooled to room temperature, diluted with water (150 mL) and extracted with dichloromethane (5×100 mL). The extract was washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The resulting orange oil was dissolved in chloroform (12 mL) and left to stand at −20° C. The resulting yellow prisms were filtered at −40° C., washed with chloroform, and filtered cold. Yield: 3.72 g (62%). MS (m/e): 228, 226 (M+), 211, 209, 183, 181, 171, 169, 147, 118, 102, 91. 1H-NMR (acetone-D6): 4.29 (t, 1H, J=6 Hz) 4.73 (d, 2H, J=6 Hz) 7.32 (m, 2H) 7.51 (d, 1H, J=8 Hz) 7.78 (dd, 1H, J=8 Hz, 2 Hz). 13C-NMR (acetone-D6): 54.74, 110.64, 119.96, 123.28, 124.57, 126.51, 128.12, 155.37.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[C:22]1([CH2:28][CH2:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(#N)C.C(OCC)(=O)C>[CH2:14]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][S:8][C:7]1[CH:6]=[CH:5][C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[CH:3][C:2]=1[NH:1][CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:15]
Reactant: O=CCCc1ccccc1
Reactant: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1NCCCc1ccccc1
Yield: 86.6 %

Procedure:
250 mg (0.62 mmol) of (E)-methyl 3-(3-amino-4-(2-(diethylamino)ethylthio)-phenyl)acrylate was suspended in acetonitrile (5 mL) and to this solution, 3-phenylpropionaldehyde (108 mg, 0.8 mmol) was added under stirring. Then, sodium triacetoxyborohydride (636 mg, 3 mmol) was added and the resulted mixture was stirred at room temperature for 3-60 hours. Water and ethyl acetate was added after removing the solvent—acetonitrile. Collecting organic layers and drying it, 229 mg of (E)-methyl 3-(4-(2-(diethylamino)ethylthio)-3-(3-phenylpropylamino)phenyl)acrylate was obtained in a form of an oily product after being purified by chromatography. Yield: 86.6%. TLC: Rf=0.6 (DCM:MeOH=9:1). HPLC: 91%; tR=9.90 min (LC/PDA: Diamonsil C18.5μ 150×4.6 mm, flow rate 1.0 mL/min, grade: 10-100% B, 18 minutes; mobile phase A: H2O; mobile phase B: acetonitrile; UV254). MS (m/z): 427 (MH)+.
Reaction SMILES: C1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4]CN1.[H-].[Na+].[CH3:16]I.[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[CH3:18][N:19]1[CH2:21][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([CH3:16])[C:13]=2[CH2:20]1
Reactant: CN(C)C=O
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN1CCc2c(n(C)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2,3,4-Tetrahydro-β-carboline (2.35 g) and NaH (60% nujol, 1.20 g) were added to anhydrous DMF and stirred at room temperature for 30 minutes. To the ice-cooled reaction solution was added methyl iodide (1.7 ml) and the reaction solution was stirred overnight. After removal of DMF by evaporation, the residue was mixed with water and extracted with chloroform. The extract was washed with water and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel. Eluates with 5% methanol/chloroform afforded 1.6 g of 2,9-dimethyl-1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1.[O:26]1[CH2:29][C:28](=O)[CH2:27]1>ClCCCl>[O:26]1[CH2:29][CH:28]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:27]1
Reactant: O=C1COC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OC1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Sodium triacetoxyborohydride (3.18 g, 15.00 mmol) and acetic acid (0.859 mL, 15.00 mmol) were added to a solution of piperidin-4-ol (1.011 g, 10 mmol) and oxetan-3-one (0.721 g, 10.00 mmol) in DCE (35 mL) and the reaction mixture was stirred at room temperature overnight. Celite was added to the sticky reaction mixture and the reaction mixture was filtered, the filtrate was concentrated in vacuo to give a brown oil. The solid was purified by flash chromatography on silica gel using an automated ISCO system (120 g column, eluting with 0-8% 2 N ammonia in methanol/dichloromethane). 1-(oxetan-3-yl)piperidin-4-ol (0.80 g) was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+]>C1(C)C=CC=CC=1.CCOCC>[CH3:11][S:12][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CSc1cc(F)ccc1C=O
Temperature: 80 °C
Reaction time: 14 h
Yield: 75.3 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (16 mL, 146 mmol) and sodium thiomethoxide (14 g, 200 mmol) in toluene (200 mL) was stirred at 80° C. for 7 h and 14 h at room temperature. The reaction mixture was diluted with ether (300 mL), washed with water (100 mL), saturated aqueous NaHCO3 (100 mL) and brine (50 mL). The aqueous layers were combined and extracted with ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to give a viscous oil. This viscous oil was dissolved in ether/hexanes (1:1, v/v) and slowly concentrated on under vacuum. The precipitated white solid was separated by filteration and dried to give 2-methylthio-4-fluorobenzaldehyde (18.7 g, 75% yield). 1HNMR (500 MHz, CDCl3) δ: 10.11 (1H, s), 7.78 (1H, dd, J=8.55, 6.11 Hz), 6.97 (1H, dd, J=10.07, 2.44 Hz), 6.91 (1H, td, J=8.54, 2.44 Hz), 2.45 (3H, s). MS calcd for C8H7FOS (M+H): 171.2. found: 171.6.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH2:5][C:4]([C:11]([O:13]C)=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[C:18]([O:17][C:15]([N:1]1[CH2:2][CH2:3][C:4]([C:7]([O:9][CH3:10])=[O:8])([C:11]([OH:13])=[O:12])[CH2:5][CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 1-tert-butyl 4,4-dimethyl piperidine-1,4,4-tricarboxylate (6.2 g, 20.5 mmol) in THF (11 mL) and CH3OH (11 mL) was added aqueous LiOH (2 N, 11 mL, 22 mmol, 1.1 equiv.). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was neutralized with HCl (1N) and was concentrated to dryness. The residue was dissolved in ethyl acetate and dried over Na2SO4 and concentrated to give 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (4.7 g, 80%), which was used without further purification. LRMS (M+H+-Boc) m/z 188.0.