Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([OH:19])[C:3]=1[OH:20].[CH2:21]1[O:23][CH2:22]1.Cl>CC(C)=O.C(OCC)(=O)C.C(O)C>[ClH:1].[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][OH:23])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([OH:19])[C:3]=1[OH:20]
Reactant: C1CO1
Reactant: Oc1cc2c(c(Cl)c1O)CCNCC2c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(C)=O
Product: OCCN1CCc2c(cc(O)c(O)c2Cl)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A 3.9 g sample of 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is slurried in 25 ml of acetone and 0.7 g (0.016 mol, 10% excess) of ethylene oxide is added. The mixture is placed in a pressure bottle and stirred at ambient temperature for about 40 hours. The reaction mixture is then heated to 60°-80° for 30 minutes, cooled and filtered. Concentration of the filtrate gives a solid which is taken up in ethyl acetate and reprecipitated with ether. The solid thus obtained is dissolved in ethanol and treated with ethereal hydrogen chloride to give 6-chloro-7,8-dihydroxy-3-(2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: Br[CH2:2][CH:3]([OH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:10]=[N+:11]=[N-:12].[Na+]>CCO.O>[N:10]([CH2:2][CH:3]([OH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N+:11]=[N-:12]
Reactant: CCOC(=O)C(O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(O)CN=[N+]=[N-]
Temperature: 90 °C

Procedure:
To a solution of ethyl 3-bromo-2-hydroxypropanoate (22.1 g, 112.0 mmol) in EtOH/H2O (1:1) was added sodium azide (10.9 g, 168.0 mmol). The reaction was stirred and heated to 90° C. for 3 days. The EtOH was removed in vacuo and the remaining aqueous solution was extracted with CHCl3 several times. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the azide as an orange oil. 1H NMR (400 MHz, d6-DMSO) δ 5.96 (d, J=5.6 Hz, 1H), 4.31-4.28 (m, 1H), 4.19-4.08 (m, 2H), 3.51-3.40 (m, 2H), 1.28-1.17 (m, 3H).
Reaction SMILES: C=C.[Cl:3][C:4]1[C:13]([CH:14]=[N:15][OH:16])=[C:12]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[C:21]([O-])(=O)[CH3:22].[Na+].Cl[O-].[Na+]>ClCCl>[Cl:3][C:4]1[C:13]([C:14]2[CH2:22][CH2:21][O:16][N:15]=2)=[C:12]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Agent: C=C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1Cl
Reaction time: 12 h
Yield: 2525.3 %

Procedure:
At 15-20° C., ethylene is introduced into a solution of 158.0 g (0.54 mol) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate and 1 l of dichloromethane for 30 minutes. After the addition of 1.6 g of sodium acetate, 454 ml of sodium hypochlorite solution were added dropwise at 10° C., while simultaneously introducing ethylene. Subsequently, ethylene was introduced at 10° C. for a further 15 minutes. The mixture was stirred for 12 hours, the phases were separated and the organic phase was washed with water, dried and concentrated. 156.5 g (90% of theory) of methyl 2-chloro-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:41])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37]Cl)=[C:30]([O:39][CH3:40])[CH:29]=1)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].[K]>CN(C)C=O>[CH2:23]([O:25][C:26](=[O:41])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[C:30]([O:39][CH3:40])[CH:29]=1)[CH3:24]
Reactant: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1

Procedure:
A mixture of 9.1 g (0.03 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 8.6 g (0.03 mole) of 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.5 g of potassium iode in 150 ml of dimethylformamide was heated on a steambath for 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an off-white solid which was recrystallized from isopropyl ether/2-propanol. The yield of the title compound was 12.7 g (77%), mp 110°-112° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:9]1[CH2:17][CH2:16][CH:12]([C:13](=[O:14])[NH2:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
85.5 g of benzyl bromide are added dropwise at RT to a mixture of 58.2 g of isonipecotamide and 69 g of K2CO3 in 275 ml of DMF and the reaction mixture is stirred for 2 hours at 50° C. It is concentrated under vacuum, the residue is taken up with water and extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 62 g of the expected product after crystallization from 300 ml of water and drying under vacuum.
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].[F:11][S:12]([F:19])=[C:13](O)[C:14]([F:17])([F:16])[F:15]>>[F:11][S:12]([F:19])=[C:13]([O:6][CH2:5][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH3:7])[C:14]([F:17])([F:16])[F:15]
Reactant: OC(=S(F)F)C(F)(F)F
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Product: CC(COC(=S(F)F)C(F)(F)F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 95 %

Procedure:
Using a method similar to example 12, 2,2-dinitropropanol and pentafluorothioacetic acid were reacted to form 2,2-dinitropropyl pentafluorothioacetate (95% yield) mp 22° C.;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20]C1C=CN=C2C=C(C3SC=CN=3)SC=12>>[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 45 %

Procedure:
Starting from compound 214 (scheme 46) and following the procedure described above for the synthesis of compound 11 (scheme 2, step 3, example 12), title compound 218 was obtained in 45% yield. MS (m/z) 371.1 (M+H).
Reaction SMILES: [F:1][CH:2]([CH:8](OC(SC)=S)[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OOC(C)(C)C)(C)(C)C.O1CCOCC1.O>C(OC(=O)C)C>[F:1][CH:2]([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC1CCC(C(OC(=S)SC)C(F)C(=O)OCC)CC1
Agent: CC(C)(C)OOC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC1CCC(CC(F)C(=O)OCC)CC1
Yield: 75.1 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 2.1 g of ethyl 2-fluoro-3-(((methylthio)carbonothioyl)oxy)-3-(4-propylcyclohexyl)propanoate (e-10), 0.5 ml of di-tert-butylperoxide, 1.2 g of DPPO and 40 ml of dioxane were added, and the resultant mixture was subjected to heating reflux for 48 hours. After cooling the resultant reaction mixture to 25° C., 100 ml of water and 100 ml of ethyl-acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, and then the resultant solution was dried over anhydrous magnesium sulfate. The resultant solution was concentrated under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of heptane and ethyl acetate (heptane:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 1.1 g of ethyl 2-fluoro-3-(4-propylcyclohexyl)propanoate (e-11) was obtained. A yield based on compound (e-10) was 74.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.ClS([N:36]=[C:37]=[O:38])(=O)=O>ClCCl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:37]([NH2:36])=[O:38])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Solvent: ClCCl
Product: NC(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.0191 mL, 0.223 mmol) dropwise at 0° C. and the reaction mixture allowed to stir for 2 h while warming to ambient temperature. The volatile components were evaporated under reduced pressure and the resulting residue was cooled to 0° C. 1.5N HCl was added and the reaction mixture stirred for an additional 2 h. The reaction mixture was adjusted to pH˜8 by the addition of aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 30 as described in general methods) to afford 1-(5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)urea (2.00 mg, 3.01%) as a white solid. LCMS (Condition 4): retention time 2.32 min, [M+1]=447.2. HPLC (Condition 28): retention time=6.13 min, purity 98.80%. 1H NMR (400 MHz, DMSO-d6) δ 4.51 (d, J=4.8 Hz, 2 H), 5.04 (t, J=4.8 Hz, 1 H), 6.10 (s, 2 H), 7.02 (dd, J=1.2 Hz, J=6.8 Hz, 2 H), 7.22-7.28 (m, 3 H), 7.43-7.51 (m, 5 H), 7.68 (dd, J=1.2 Hz, J=7.6 Hz, 1 H), 7.85-7.92 (m, 2 H), 8.24 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 8.64 (d, J=2.4 Hz, 1 H), 8.94 (s, 1 H).
Reaction SMILES: [C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:27][N:19]1[C@H:20]2[C@@:15]([CH3:24])([C:14]3[CH:25]=[CH:26][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[CH:12][C:13]=3[CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]1=[O:23]
Reactant: CC(C)(C)O
Reactant: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc5ccccc45)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (22 mg, 0,065 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (22 mg, 0.19 mmol). Methyl iodide (0.012 mL, 0.19 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 16 mg (70%) of the title compound as a yellow solid, upon trituration from diethyl ether/hexanes. mp 172°-173°. FDMS: m/e=353.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH:24][C:35]([NH:34][C:32]4[N:31]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=4)=[O:36])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(N)nc34)c3ccccc23)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 2-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly pink solid (70 mg, 80%). 1H-NMR (DMSO-d6), δ (ppm), J (Hz): 1.29 (s, 9H, tert-Bu), 6.31 (d, 1H, Harom, J=5.5 Hz), 6.41 (s, 1H, Harom), 7.22 (d, 1H, Harom, J=8.3 Hz), 7.44 (t, 1H, J=7.0 Hz), 7.54-7.65 (m, 6H, Harom), 7.85 (d, 1H, Harom, J=8.3 Hz), 7.88-7.91 (m, 2H, Harom), 8.06 (d, 1H, Harom, J=8.6 Hz), 8.76 (s, 1H, NHurea), 9.04 (s, 1H, NHurea), 12.58 (s, 1H, NHlactame). 13C-NMR (DMSO-d6), δ (ppm), J (Hz): 30.08 (tert-Bu), 31.92 (tert-Bu), 95.69, 106.46, 116.05, 118.94, 119.36, 121.56, 122.27, 124.12 (2*C), 126.32, 126.52, 126.55, 127.11, 127.97, 129.17 (2*C), 131.22, 137.15, 138.59, 142.95, 143.56, 146.22, 151.71, 152.33, 152.72, 157.12, 160.68. HRMS (EI): m/z [M+H] calcd for C31H2O8O3: 561.2357. found: 561.2351.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([C:33]=2[N:34]2[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40]C(=O)OC(C)(C)C)[CH2:35]2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])[N:20]=1>C(Cl)Cl>[NH2:40][C@H:36]1[CH2:37][CH2:38][CH2:39][N:34]([C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][C:24]=2[NH:23][C:21]([C:19]2[N:20]=[C:16]([C:10]3[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=3[F:8])[S:17][CH:18]=2)=[O:22])[CH2:35]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)quinolin-4-yl]piperidin-3-yl}carbamate (57.4 mg, 0.101 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (25.4 mg, 54%). LCMS calc. for C24H22F2N5OS (M+H)+: m/z=466.1. found 466.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>CN(C=O)C>[OH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCCO)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 38.5 %

Procedure:
Ex-39A: A solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-13C, 500 mg, 2.13 mmol) in DMF (20 mL) was treated with potassium carbonate (589 mg, 4.26 mmol) followed by the addition of 3-bromo-propan-1-ol (356 mg, 2.56 mmol). The reaction mixture was heated to 80° C. for 2 h followed by another addition of potassium carbonate (294 mg, 2.13 mmol) and 3-bromo-propan-1-ol (296 mg, 2.13 mmol). The reaction mixture was stirred for an additional 45 minutes, quenched with water (15 mL), and extracted with ethyl acetate (2×25 ml). The organic phase was washed with brine, dried over sodium sulfate, and concentrated to a beige oil. The oil was purified by column chromatography (elution: 30, 50, and 80% ethyl acetate in hexane) to yield 240 mg (38%) of 2-(3-hydroxypropoxy)-4-methoxy-5-thiophen-2-ylbenzaldehyde as an off-white solid. 1H-NMR (300 MHz, CDCl3) 10.21 (s, 1H), 8.02 (s, 1H), 7.41 (br d, 1H, J=3.9 Hz), 7.28 (d, 1H, J=5.10 Hz), 7.06 (dd, 1H, J=3.0, 5.7 Hz), 6.48 (s, 1H), 4.24 (t, 2H, J=7.0 Hz), 3.92 (s, 3H), 3.88 (br s, 2H), 2.11 (q, 2H, J=7.0 Hz).
Reaction SMILES: C1C=CC(CCC[N:10]2CCN(CCOC(C3C=CC(F)=CC=3)C3C=CC(F)=CC=3)CC2)=CC=1.CC([O:37][C@@H:38]1[C@@:50]2(C)[O:51][C@](C=C)(C)CC(=O)[C@:49]2(O)[C@@:41]2(C)[C@@H](O)C[CH2:44][C:45](C)(C)[C@@H:40]2[C@@H:39]1O)=O>>[NH2:10][CH2:44][CH2:45][C:40]1[CH:41]=[CH:49][C:50]([OH:51])=[C:38]([OH:37])[CH:39]=1
Reactant: C=C[C@@]1(C)CC(=O)[C@]2(O)[C@@]3(C)[C@@H](O)CCC(C)(C)[C@@H]3[C@H](O)[C@H](OC(C)=O)[C@@]2(C)O1
Reactant: Fc1ccc(C(OCCN2CCN(CCCc3ccccc3)CC2)c2ccc(F)cc2)cc1
Product: NCCc1ccc(O)c(O)c1
Temperature: 37 °C
Reaction time: 1 h

Procedure:
[3H]DA uptake was measured in cultures at day 7, and all the solutions were maintained at 37° C. The growth medium was removed, and the cultures were rinsed twice with 0.25 ml of uptake buffer, which consists of HBSS (Gibco 11201-092) supplemented with 28 mM glucose, 15 mM HEPES, 1 mM ascorbic acid (an antioxidant), and 0.5 nM pargyline (a monoamine oxidase inhibitor). The cultures were then incubated with 0.25 ml of fresh uptake buffer containing 50 nM [3H]DA (NEN/DuPont) for 20 min at 37° C. [3H]DA uptake was stopped by removing the incubation mixture, and cells were then washed twice with 0.5 ml of the uptake buffer at room temperature. To release [3H]DA from the cells, the cultures were lysed with 0.2 ml of 0.1 N NaOH for 1 h at room temperature, the lysate was then added to 1 ml of Microscint-20 (Packard 6013621), and counted for radioactivity in a microplate scintillation counter (Packard TopCount, NXT). Background values were obtained by adding to the uptake buffer 0.5 mM GBR-12909, a specific inhibitor of the high-affinity uptake pump of the dopaminergic neurons, and were usually <5% of the 3H uptake in untreated control cultures. Forskolin (Fk, 25 μM) was employed as a positive control.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:18][O:19][CH2:20][CH2:21]Br.[OH-].[Na+].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:18][O:19][CH2:20][CH2:21][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: COCCBr
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 21 %

Procedure:
To a solution of benzyl 4-hydroxy-1-piperidinecarboxylate (1.0 g) in toluene/aqueous 2N sodium hydroxide solution (10 mL/10 mL) was added tetrabutylammonium bromide (550 mg) and methoxyethyl bromide (1.2 mL) and the mixture was stirred at 60° C. for 2.5 hours and then stirred at 80° C. for 17 hours. To the reaction mixture was added sodium hydroxide (0.95 g) and methoxyethyl bromide (1.2 mL) and the mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, to the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate=75/25 to 40/60) to give benzyl 4-(2-methoxyethoxy)-1-piperidinecarboxylate (266 mg, yield: 21%) as a pale yellow liquid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[CH:27][C:26]=2[C:34]([F:37])([F:36])[F:35])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([NH:33][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=2)[CH3:32])=[O:15])=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]
Reactant: CC(N)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Reactant: N=C(N)c1ccc(NC(=O)CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)CC(=O)Nc1ccc(C(=N)N)cc1)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
134.1 mg (0.4 mmol) of N-(4-carbamimidoyl-phenyl)-malonamic acid*trifluoro-acetic acid salt (intermediate 4) was dissolved in absolute DMF and to this solution 118.5 mg (0.4 mmol) of the amine from step 2, 509 mg (0.8 mmol) 1-propane-phoshonic-acid-anhydride and 51.7 mg (0.4 mmol) N,N-diisopropy-ethyl-amine were added. After stirring for 24 h at ambient temperature the reaction mixture was filtered, evaporated to dryness and purified by preparative HPLC. Yield 45 mg (18%), colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@H:25]3[C:38]4[CH:37]=[CH:36][C:35]5[CH2:34][NH:33][CH2:32][CH2:31][C:30]=5[C:29]=4[CH2:28][CH2:27][CH2:26]3)[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:39](=O)[CH:40]([CH3:42])[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@H:25]3[C:38]4[CH:37]=[CH:36][C:35]5[CH2:34][N:33]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:32][CH2:31][C:30]=5[C:29]=4[CH2:28][CH2:27][CH2:26]3)[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC=CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)[C@@H]1Cc1cn([C@@H]2CCCc3c2ccc2c3CCNC2)nn1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CN1CCc2c(ccc3c2CCC[C@H]3n2cc(C[C@@H]3C(=O)NC=CN3S(=O)(=O)c3ccc(Cl)c(Cl)c3)nn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((R)-4-(3,4-dichlorophenylsulfonyl)-3-((1-((R)-1,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)methyl)-3,4-dihydropyrazin-2(1H)-one (220 mg, 0.384 mmol) and isobutyraldehyde (83 mg, 1.15 mmol) in 3 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (163 mg, 0.768 mmol) and the resulting solution was stirred at RT overnight. The reaction mixture was quenched with sat. NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to dryness. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:7 to 100:12 to 100:14) afforded the title compound as a white solid.