Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:25]1[CH:26]=[N:27][N:28]([CH:30]([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH3:31])[CH:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:26]=[N:27][N:28]([CH:30]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH3:31])[CH:29]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(C(C)n2cc(Br)cn2)cc1
Reactant: Cc1cc(Nc2ncccn2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C(C)n2cc(-c3cc(C)cc(Nc4ncccn4)c3)cn2)cc1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
A mixture of N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (100 mg, 0.321 mmol), methyl 4-(1-(4-bromo-1H-pyrazol-1-yl)ethyl)benzoate (139 mg, 0.450 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), X-phos (15 mg, 0.032 mmol), and cesium carbonate (314 mg, 0.964 mmol) was diluted with 1,4-dioxane (3 mL) and water (0.3 mL) at ambient temperature. The mixture was stirred for 5 minutes under a subsurface argon sparge, after which time the mixture was heated to 90° C. and stirred under an argon atmosphere for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 mL) and water (25 mL). The organic layer was separated and washed with water (25 mL) and then brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% [5% methanol in ethyl acetate]/hexanes) to afford methyl 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzoate. MS ESI calcd. for C24H24N5O2 [M+H]+ 414. found 414. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.46 (d, J=4.5 Hz, 2H), 8.24 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.80 (s, 1H), 7.72 (s, 1H), 7.41 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.01 (s, 1H), 6.80 (t, J=5.0 Hz, 1H), 5.76-5.70 (m, 1H), 3.82 (s, 3H), 3.27 (s, 3H), 1.83 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[C:42](=[O:44])=[O:43]>>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[C:11](=[O:21])[N:12]3[C:17](=[C:8]([C:6](=[O:7])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:9]=2)[C:16]2[S:18][C:19]([C:42]([OH:44])=[O:43])=[CH:20][C:15]=2[CH:14]=[CH:13]3)=[CH:23][CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Reactant: O=C=O
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(C(=O)O)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with carbon dioxide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].Br[CH:35]1[CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[CH:35]1([S:9]([C:7]2[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])(=[O:11])=[O:10])[CH2:38][CH2:37][CH2:36]1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: BrC1CCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)C2CCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 115 °C

Procedure:
Under argon, sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (150 mg, 65 μmol; purity about 21%) was suspended in a pressure-proof glass tube in DMF (1 ml). Molecular sieve (4 Å, 20 mg) and bromocyclobutane (100 μl, 1088 μmol, 16.7 eq.) were added. The sealed tube was heated at 115° C. for 15 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column; mobile phase: acetonitrile/water+0.1% TFA). After lyophilization, the title compound was obtained as a solid (15.5 mg, purity according to LC-MS 90%, 41% of theory).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[C:15]([CH3:32])[CH:14]=2)=[N:5][C:4]=1[C:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:23][CH2:24]3)=[C:15]([CH3:32])[CH:14]=2)=[N:5][C:4]=1[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1=CCNCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1CCNCC1
Yield: 86.7 %

Procedure:
A mixture of 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxamide (100 mg), ethanol (3.9 mL), and tetrahydrofuran (1 mL) was reacted using a continuous hydrogenation reaction device (H-Cube (registered trademark); manufactured by ThalesNano) under the conditions of CatCart (registered trademark) 10% palladium-supported carbon (manufactured by ThalesNano), a flow rate of 1 mL/min, a temperature of 70° C., and a pressure of 1015 psi. The solvent was evaporated under reduced pressure to obtain 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-yl)pyrazine-2-carboxamide (87 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH:18]([Mg]Br)=[CH2:19]>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH:18]=[CH2:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.00 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 350 ml of tetrahydrofuran, cooled to 0° C. is added 130.43 ml of 1.0M vinylmagnesium bromide in tetrahydrofuran over 15 minutes. The reaction mixture is stirred at 0° C. for 30 minutes. The reaction mixture is quenched at 0° C. with 50 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried (Na2SO4) and concentrated in vacuo to afford a residue which is purified by column chromatography on silica gel using 1:1 ethyl acetate-hexane to give 4.81 g of the desired product, as a white solid, MP 141° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[C:19]1(=[CH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:20]1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[C:19]1([CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:20]1
Reactant: CCOC(C)=O
Reactant: COC(=O)C=C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(CC(=O)OC)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
240 ml (1.70 mol) of diisopropylamine were dissolved in 700 ml of abs. THF, the mixture was cooled to −40° C. and 681 ml (1.7 mol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The solution was stirred at −40° C. for 30 min and then cooled to −78° C., and a solution of 166.6 ml (1.7 mol) of ethyl acetate p.a. in 200 ml of abs. THF was added. After the end of the addition, the mixture was stirred at −78° C. for another 30 min 159 g (crude product, about 1.42 mol) of methyl cyclopropylideneacetate, dissolved in a little abs. THF, were then added dropwise. The reaction mixture was stirred at −78° C. for 1 h and then, via −40° C., slowly warmed to about 0° C., and a saturated aqueous ammonium chloride solution was finally added. The mixture was extracted with ethyl acetate and the organic phase was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 9:1). This gave 109.5 g of the target compound which was contaminated by the diethyl ester derivative and was not purified any further.
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[SH:48][C:49]1[N:53]=[C:52]([C:54]2[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=2)[NH:51][N:50]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[CH:2]([S:48][C:49]3[NH:53][C:52]([C:54]4[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=4)=[N:51][N:50]=3)[C:7](=[O:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Reactant: Oc1ccc(-c2nc(S)n[nH]2)cc1
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Sc3nnc(-c4ccc(O)cc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one example C(40), was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 4H-3-mercapto-5-(4-hydroxyphenyl)[1,2,4]-triazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Zn]CC)C.Br[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][CH:34]([NH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=3)=[CH:44][CH:43]=1)=[O:41])[CH2:33][CH2:32]2.[CH3:55][N:56]1CCCC1=O>CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[Zn+2]>[C:55]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][CH:34]([NH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=3)=[CH:44][CH:43]=1)=[O:41])[CH2:33][CH2:32]2)#[N:56]
Reactant: O=C(NC1CCc2cc(Br)ccc2C1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[Zn]CC
Product: N#Cc1ccc2c(c1)CCC(NC(=O)c1ccc(-c3ccc(F)cc3)cc1)C2
Temperature: 55 °C

Procedure:
A degassed solution of Pd(OAc)2 (0.078 g, 0.35 mmol) and tri-o-tolylphosphine (0.422 g, 1.39 mmol) in N-methylpyrrolidinone (5 mL) is heated at 55° C. for 30 minutes under a nitrogen atmosphere. To this solution is added diethyl zinc(II) (1.0M in hexane, 0.69 mL, 0.69 mmol) and the mixture is maintained at 55° C. for an additional 30 minutes. A premixed solution of 4′-fluoro-biphenyl-4-carboxylic acid (6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, 2, (1.470 g, 3.464 mmol) and Zn(CN)2 (0.405 g, 3.46 mmol) in N-methyl pyrrolidinone (5 mL) is added to the above mixture via cannula. The reaction mixture is then heated at 60° C. overnight. Once cooled, the desired product is then precipitated by adding MeOH to afford 1.43 g (quantitative yield) of an off-white solid. 1H NMR (300 MHz, DMF-D7) δ 8.78 (d, J=7.5 Hz, 1H), 8.28 (d, J=8.7 Hz, 2H), 7.98-8.04 (m, 4H), 7.76-7.81 (m, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.51-7.54 (m, 1H), 4.56 (m, 1H), 3.42-3.50 (m, 1H), 3.16-3.24 (m, 3H), 2.32-2.42 (m, 1H), 2.06-2.20 (m, 1H); 13C NMR (75 MHz, DMF-D7) δ 166.2, 162.6, 142.3, 142.0, 138.1, 134.2, 132.8, 130.7, 129.5, 129.4, 128.4, 126.9, 119.8, 116.3, 116.0, 109.7, 45.9, 30.4, 28.7, 28.0; LRMS: 371.3 (M+H).
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:25]=2)[N:16]=1.[OH-].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.CO.O1CCCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:26]1[N:25]=[C:24]([C:17]2[N:16]=[C:15]([CH3:1])[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCCc1cc(Cl)nc(-c2cccc(Oc3ccccc3Cl)n2)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1cc(C)nc(-c2cccc(Oc3ccccc3Cl)n2)n1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To tetrahydrofuran (30 ml) were added diethyl malonate (1.35 g) and 60% oilly sodium hydride (0.34 g), and then 4-chloro-2-(6-o-chlorophenoxy-2-pyridinyl)-6-n-propylpyrimidine (2 g). The mixture was heated under refluxing for 30 minutes. Sodium hydroxide (0.72 g) solution in water (10 ml) and methanol (10 ml) were added thereto, and the mixture was further heated under refluxing for 20 minutes. After the mixture was left to stand until it was cooled to room temperature, sulfuric acid (1.2 g) was added dropwise thereto. The mixture was heated under refluxing for 30 minutes and left to stand to room temperature. 1-N aqueous sodium carbonate solution was added until a mixture was neutralized, and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography (eluent; n-hexane: ethyl acetate=2:1 in volume) to give 2-(6-o-chlorophenoxy-2-pyridinyl)-4-methyl-6-n-propylpyrimidine (1.45 g, yield 74%).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: O
Product: N[C@@H]1CCC[C@@H]1C1CCCCC1
Yield: 33.9 %

Procedure:
Using rhodium-on-charcoal catalyst in a Paar shaker, 12.6 g of cis-2-phenylcyclopentylamine hydrochloride, M.P. 204°-206° C in 100 ml of water is hydrogenated. In 20 hours when the theoretical amount of hydrogen has been taken up the catalyst is removed by filtration, the filtrate made basic with sodium hydroxide solution, and the resulting precipitate is extracted into ether. After evaporation of the ether the residue is distilled, M.P. 100°-102° C (6.0 mm). The hydrochloride salt is prepared and recrystallized from isopropanol-ether to give 4.4 g of cis-2-(cyclohexyl)cyclopentylamine hydrochloride, M.P 174°-176° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)[N:6]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C)C=O>[CH3:22][O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([N:7]1[C:8]([CH3:10])=[CH:9][C:5]([O:4][CH2:3][CH2:2][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:6]1)[CH:20]=[CH:19]2
Reactant: COc1ccc2cc(-n3nc(OCCCl)cc3C)ccc2c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: COc1ccc2cc(-n3nc(OCCN4CCOCC4)cc3C)ccc2c1
Yield: 61 %

Procedure:
A solution of 3-(2-chloroethoxy)-5-methyl-1-(6-methoxynaphthalen-2-yl)-1H-pyrazol (0.63 g, 2 mmol) and morpholine (0.96 g, 8 mmol) in dimethylformamide (10 ml) was heated to 95° C., in a nitrogen atmosphere, during 20 hrs. Next, it was cooled, the DMF was evaporated in a rotavapor and water and dichloromethane was added to the residue. The organic phase was washed with water and, subsequently, it was extracted with HCl 2N several times. The collection of acidic waters was basified by the addition of NaOH 20% and it was extracted with dichloromethane, which was dried over Na2SO4, filtered and evaporated, thereby leaving a residue of 448 mg of 4-{2-[1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine (yield: 61%) in the form of a colourless oil.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH:35]=O)[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31]1
Reactant: CCCC[C@H]1CC[C@H](C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution, cooled to -20° C., of 398 g of tetrabromomethane in 1 l of methylene chloride was treated dropwise under nitrogen gasification within 30 minutes with a solution of 629.6 g of triphenylphosphine in 1 l of methylene chloride. The mixture was subsequently stirred at -10° C. for a further 30 minutes, then treated dropwise within 30 minutes with a solution of 101 g of trans-4-butylcyclohexanecarboxaldehyde in 500 ml of methylene chloride and stirred at -5° C. for a further 2 hours. The mixture was poured into 4 l of hexane, the resulting mixture was stirred at -20° C. for 1 hour and then the precipitate was filtered off under suction and rinsed well with 1 l of cold (-20° C.) hexane. The filtrate was concentrated to a volume of about 1 l on a rotary evaporator, diluted with 2 l of hexane, again concentrated to a volume of about 1 l and stirred at -20° C. for a further 30 minutes. The precipitate was filtered off under suction and rinsed well with 700 ml of cold (-20° C.) hexane. The filtrate was freed from solvent on a rotary evaporator and the resulting yellow oil (195 g) was filtered chromatographically on silica gel with about 3 l of hexane. The eluate was evaporated up to constant weight on a rotary evaporator, there being obtained 171.3 g (88.1%) of trans-1-(2,2-dibromovinyl)-4-butylcyclohexane as a colourless liquid; Rf-value (hexane) 0.55.
Reaction SMILES: [H-].[Na+].[I-].[Na+].[CH2:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>CN(C)C=O.O>[CH2:5]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 67 h
Yield: 53 %

Procedure:
To a stirred mixture of about 39.7 g of about 50% sodium hydride, about 13.5 g of sodium iodide and about 208.58 g of tetradecylbromide in about 750 ml of dimethylformamide at about 0° C. was added a solution of about 125 g of ethyl p-hydroxybenzoate in about 400 ml of dimethylformamide over about 1/2 hour. The mixture was stirred at room temperature for about 67 hours and then poured into about 2 liters of water. The solid was collected, washed with water, mixed with hot (about 50° C.) ethyl acetate, washed with water and dried. The solvent was removed and the residue recrystallized from ethanol, giving about 144.57 g of the desired title compound, mp 34°-35° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([O:15][CH3:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:12][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(N)cc1F
Yield: 97.7 %

Procedure:
Methyl 2-fluoro-5-methoxy-4-nitrobenzoate (549 mg; 1.13 mmol; 1 eq.) was dissolved in MeOH (50 mL). The resulting solution was injected on a flow hydrogenation reactor (H-Cube), adapted with Pd/C cartridge (44 mm), a flow of 1 mL/min, a temperature of 60° C. and the full H2 option enabled. Solvents were evaporated, affording the title product as an off-white solid (220 mg; 97%). LC/MS (Method B): 200.0 (M+H)+. HPLC (Method A) Rt 3 min (Purity: 91.9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][NH:18][CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[N:18]([O:17][CH3:16])[CH3:19])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (3.5 g, 17 mmol) in DMF (50 mL) was added O,N-dimethyl-hydroxylamine hydrochloride (3.4 g, 34 mmol), triethylamine (9.6 mL, 69 mmol), HATU (13.4 g, 34.6 mmol) and DCM (125 mL). After stirring for 16 h, saturated NaHCO3 solution and ethyl acetate were added. The aqueous portion was extracted three times with ethyl acetate. The combined organic fractions were dried (Na2SO4) and concentrated and the crude product was purified using RP HPLC (basic conditions) to provide the title compound (3.5 g, 83%) MS (ESI): mass calcd. for C11H20N2O4, 244.1; m/z found, 189.1 [M-t-Bu]+. 1H NMR (CDCl3): 4.14-4.03 (m, 2H), 4.05 (t, J=8.7 Hz, 2H), 3.66 (s, 3H), 3.63-3.59 (m, 1H), 3.21 (s, 1H), 1.43 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]3[C:21]=2[C:16](=[C:17]2[CH:33]=[CH:32][CH:31]=[CH:30][C:18]2=[CH:19]3)[C:15]1=[O:34])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]([CH3:11])[CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]3[C:21]=2[C:16](=[C:17]2[CH:33]=[CH:32][CH:31]=[CH:30][C:18]2=[CH:19]3)[C:15]1=[O:34]
Reactant: COc1ccc2c3c(c4ccccc4cc13)C(=O)N(CCN(C)CCNC(=O)OC(C)(C)C)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c3c(c4ccccc4cc13)C(=O)N(CCN(C)CCN)C2=O

Procedure:
Method (ii)—Removing Boc protection by Preparing Trifluoroacetic salt: The trifluoroacetic salt of 2-{2-[(2-aminoethyl)methylamino]ethyl}-6-methoxy-1,2-dihydro-3H-dibenzo[de,h]isoquinoline-1,3-dione was prepared by stirring (2-{[2-(6-Methoxy-1,3-dioxo-1H,3H-dibenzo[de,h]isoquinolin-2-yl)-ethyl]-methyl-amino}-ethyl)-carbamic acid tert-butyl ester with 50% trifluoroacetic acid in DCM for 40 minutes. The reaction was quantitative.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]2[C:12]=1[C:13]([C:22]#[N:23])=[CH:14][NH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:24][NH:25]CCC(C1C=C2C(=CC=1)NC=C2C#N)C1C=CC=CC=1>>[CH3:21][O:20][C:18]1[CH:17]=[C:16]2[C:12]([C:13]([C:22]#[N:23])=[CH:14][NH:15]2)=[C:11]([CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2][NH:25][CH3:24])[CH:19]=1
Reactant: COc1cc(C(CCO)c2ccccc2)c2c(C#N)c[nH]c2c1
Reactant: CNCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Product: CNCCC(c1ccccc1)c1cc(OC)cc2[nH]cc(C#N)c12

Procedure:
6-Methoxy-4-(3-methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile CXXXII (90 mg) was prepared from 4-(3-hydroxy-1-phenyl-propyl)-6-methoxy-1H-indole-3-carbonitrile using the procedure described above for preparation of 5-(3-Methylamino-1-pheny-propyl)-1H-indole-3-carbonitrile LXVI. MS (M+H)=320.