Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N12CCN(CC1)CC2.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>ClCCl.C(Cl)(Cl)Cl>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH:1][CH2:2][CH2:3][C:4]2([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH2:14][CH2:13]3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNS(=O)(=O)c4ccc(Cl)cc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 18) (199 mg) in dichloromethane (3 mL) were added 1,4-diazabicyclo[2.2.2]octane (100 mg) and p-chlorobenzenesulfonyl chloride (100 mg) successively. The solution was stirred at room temperature for 2 hours. The reaction solution was diluted with chloroform, washed in turn with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3)] to give the title compound (181 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.C(N(CC)CC)C.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[O:20]=[C:14]1[CH:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:35])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)N4CCOCC4)ccc3C2=O)C(=O)N1
Reaction time: 4 h
Yield: 20.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and triethylamine (0.30 mL, 2.2 mmol) in acetonitrile (10 mL) was added morpholine-4-carbonyl chloride (012 mL, 1.05 mmol) at room temperature under nitrogen. After 4 h, the reaction mixture was filtered and rinsed with acetonitrile (30 mL) and the filtrate was concentrate on the rota-yap. The residue was stirred with 20 mL of acetonitrile and water mixture (1:1). The resulted suspension was filtered to give morpholine-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.08 g, 20% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 μm; gradient CH3CN/0.1% aq H3PO4, 10 min, 1.0 mL/min, 4.8 min (96%); mp: 208-210° C.; 1H NMR (DMSO-d6) δ 1.92-2.07 (m, 1H, CHH), 2.39 (qd, J=4.4, 13.3 Hz, 1H, CHH), 2.55-2.66 (m, 1H, CHH), 2.84-2.99 (m, 1H, CHH), 3.27-3.32 (m, 4H, CH2+CH2), 3.52-3.59 (m, 4H, CH2+CH2), 4.25-4.49 (m, 4H, CH2+CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CHN), 7.22 (t, J=5.8 Hz, 1H, Ar), 7.40 (d, J=7.9 Hz, 1H, Ar), 7.47 (s, 1H, NH), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.20, 43.54, 43.86, 47.10, 51.56, 65.92, 121.88, 122.77, 126.89, 130.11, 142.23, 145.28, 157.57, 168.02, 171.01, 172.86; LCMS: MH=387; Anal Calcd for C19H22N4O5+0.6H2O: C, 57.45; H, 5.89; N, 14.10. Found: C, 57.10; H, 6.07; N, 13.97.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1)[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>CC#N>[Cl:19][C:4]1[C:5]([C:8]([F:10])([F:11])[F:9])=[N:6][NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cc(C(F)(F)F)n[nH]1
Solvent: CC#N
Product: CCc1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-ethyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield title compound
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][NH:13][CH2:14][CH2:15][C:6]2=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]12[CH2:38][CH2:37][CH2:36][C:34]3[C:35]1=[C:30]([CH:31]=[CH:32][CH:33]=3)[NH:29][C:28]2=[O:39]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][N:13]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]34[CH2:38][CH2:37][CH2:36][C:34]5[C:35]3=[C:30]([CH:31]=[CH:32][CH:33]=5)[NH:29][C:28]4=[O:39])[CH2:14][CH2:15][C:6]2=1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)CCN(CCCCC12CCCc4cccc(c41)NC2=O)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A 295 mg (1.46 mmol) portion of 6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 404 mg (2.91 mmol) of potassium carbonate were added to 7 ml of DMF solution containing 300 mg (0.97 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the thus obtained oil was purified by a silica gel column chromatography (80 cc; elution by chloroform-methanol=15:1) and recrystallized from acetone-diisopropyl ether to obtain 369 mg of the title compound (88% in yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]1>CS(C)=O>[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]3)[CH:23]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1cccc(Nc2ncc(Br)c(Nc3ccccc3)n2)c1
Reactant: CN1CCCC(CCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCCC(COc2cccc(Nc3ncc(Br)c(Nc4ccccc4)n3)c2)C1
Yield: 14.2 %

Procedure:
A mixuture of potassium carbonate (160 mg, 1.2 mmol), 4-anilino-5-bromo-2-(3-hydroxyanilino)pyrimidine (Method 10, 200 mg, 0.6 mmol) and 3-chloromethyl-1-methylpiperidine (obtained as described in Eur. J. Med. Chem. 1994, 29, 967–73; 0.11 ml, 0.62 mmol) in DMSO (2 ml) were heated at 100° C. for 18 hours. Silica (1 g) was added and volatile material was removed by evaporation. The residue was loaded onto a Varian Mega Bond Elut column and the column was eluted with 0–10% 2.0 M methanolic ammonia solution to give the product as a brown solid (40 mg, 15%). NMR: 1.0 (m, 1H), 1.4 (m, 1H), 1.6 (m, 3H), 1.8 (m, 2H), 2.1 (s, 3H), 2.6–2.8 (m, 2H), 3.6 (m, 2H), 6.4 (d, 1H), 7.0–7.4 (m, 6H), 7.6 (m, 2H), 8.2 (s, 1H), 8.5 (s, 1H), 9.2 (s, 1H); MS (MH+): 468.5, 470.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.N1CCCC1>CO>[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:13][CH2:14]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21

Procedure:
The synthesis of compound 19A-19D is outlined in Scheme 19. The 2′-hydroxyacetophenone 1.1a was condensed with benzyl 4-oxopiperidine-1-carboxylate (19.1) in refluxing methanol in the presence of pyrrolidine to provide N-Cbz-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one (19.2). Conversion of the ketone 19.2 to the enol triflate derivative 19.3 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Conversion of the enol triflate 19.3 to the corresponding boron derivative 19.4 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2]. Suzuki type coupling of the boronate derivative 19.4 with tert-butyl 4-bromophenylcarbamate 19.5 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride, and an aqueous solution of sodium carbonate afforded the tert-butyloxycarbonyl (Boc) protected aniline derivative 19.6. Acidic hydrolysis of 19.6 provided the aniline derivative 19.7 which reacted with acyl chlorides 19.8a, 19.8b, isopropylsulfonyl chloride (6.5b) or ethyl isocyanate (19.11) to give the corresponding amide derivatives 19.9, sulfonamide derivative 19.10 or urea derivative 19.12, respectively. The derivatives 19.9, 19.10 and 19.12 were converted to compounds 19A-19D by treatment with iodotrimethylsilane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: COC(=O)c1cccc(N=C=O)c1
Product: COC(=O)c1cccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Yield: 90 %

Procedure:
Example 15 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and methyl 3-isocyanatobenzoate (0.0241 g) to give the title compound (0.037 g). LC-MS (System A): Rt 2.32 mins, Mass Spectrum m/z 452 [MH+].
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:21])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[C:5]([Cl:3])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC(=O)Cl
Reaction time: 8 h

Procedure:
C 18 resin: Pentadecanoyl chloride was synthesized by reacting 10 ml of 2 M thionyl chloride in 10 ml of toluene with 1.5 gm pentadecanoic acid. After 40 minutes of refluxing, the remaining thionyl chloride and toluene were removed by distillation. 4 gm of the 3-amino-propyl resin was then incubated overnight with the freshly prepared pentadecanoyl chloride in pyridine. The next day, the resin was twice washed with methylene chloride and then three times more with methanol and dried.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(C(C)C)CC)(C)C.[CH:19]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][N:34]=[C:33]3[SH:41])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[C:36]([C:37]([F:38])([F:40])[F:39])=[N:35][N:34]=[C:33]3[S:41][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: FC(F)(F)c1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1nnc(C(F)(F)F)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 60 °C
Yield: 37.3 %

Procedure:
Ethyl 2-bromo-2-methylpropanoate (89 μL, 0.596 mmol) and diisopropylethylamine (0.31 mL, 1.789 mmol) were added to a solution of 4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.596 mmol) in DMF (1.2 mL) and the mixture heated at 60° C. for 20 hours. The mixture was concentrated, acidified with HCl (1M aqueous, 2 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by column chromatography (0-25% EtOAc/hexanes) to provide ethyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a clear oil (0.1 g, 37%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10]Cl.[OH:12][C:13]1[C:22]([C:23]#[N:24])=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH3:25])=[N:20]2)=[CH:15][CH:14]=1>CC(C)=O>[CH3:8][O:9][CH2:10][O:12][C:13]1[C:22]([C:23]#[N:24])=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH3:25])=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc2ccc(O)c(C#N)c2n1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COCOc1ccc2ccc(C)nc2c1C#N
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere, triethylamine (0.034 mL, 0.235 mmol) and chloromethyl methyl ether (0.018 mL, 0.235 mmol) were added to a solution of 5b (0.0200 g, 0.109 mmol) in acetone (8 mL). The reaction was stirred for 1 h. The solvent was evaporated and the remaining residue was dissolved in chloroform, which was washed with brine, dried over Na2SO4, and evaporated to afford 8b (0.0236 g, 0.106 mmol, 97%) as a white solid: 1H NMR (CDCl3) δ 8.02 (1H, d, J=8.0 Hz), 7.93 (1H, d, J=9.2 Hz), 7.48 (1H, d, J=9.2 Hz), 7.29 (1H, d, J=8.4 Hz), 5.43 (2H, s), 3.58 (3H, s), 2.79 (3H, s); 13C NMR (CDCl3) δ 162.4, 161.8, 148.7, 135.9, 133.4, 121.8, 121.7, 114.6, 114.9, 95.1, 56.9, 25.7; FTIR (neat) 2924, 2216, 1612, 1504, 1248, 1161, 1143, 1061, 984, 924, 839 cm−1; MS (ESI) m/z calculated for (C13H12N2O2+H)+ 229, found 229; HRMS (ESI) m/z calculated for (C13H12N2O2+H)+ 229.0978, found 229.0996.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26])=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:21][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]#[N:26])[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: N#Cc1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: N#Cc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-formylbenzonitrile was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 2-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,4-diazepan-1-yl]methyl]benzonitrile.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1>O>[CH:12]1([CH2:11][C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:9][OH:8])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCC1

Procedure:
(S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopentylpropan-2-ylcarbamate (2.9 g, 8.1 mmol) was treated with 1 M Bu4NF/THF (24.3 mL) at 0° C. for 1 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×40 mL). The organic layers were washed with saturated aqueous brine, dried over MgSO4, and evaporated to give crude (S)-tert-butyl 1-cyclopentyl-3-hydroxypropan-2-ylcarbamate that was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 4.60 (brs, 1H), 3.68 (m, 2H), 3.52 (m, 1H), 1.81 (m, 3H), 1.60 (m, 3H), 1.50 (m, 3H), 1.44 (s, 9H), 1.09 (m, 2H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[Br:22].[NH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]>>[Br:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][NH:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: COC(=O)COc1ccc(C)cc1Br
Agent: CC(C)C[AlH]CC(C)C
Product: Cc1ccc(OCCNCCNS(=O)(=O)c2cccc3cnccc23)c(Br)c1

Procedure:
By following a similar procedure as described in Example 1, DIBAL-H reduction of (2-bromo-4-methyl-phenoxy)-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a clear gum. ESIMS: m/z 464 [(M+H)+, 79Br], 466 [(M+H)+, 81Br].
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[C:40]([O:41][CH3:42])=[CH:39][C:28]2[CH2:29][C:30](=[O:38])[N:31]([CH2:34][CH2:35][CH2:36]Cl)[CH2:32][CH2:33][C:27]=2[CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[C:40]([O:41][CH3:42])=[CH:39][C:28]2[CH2:29][C:30](=[O:38])[N:31]([CH2:34][CH2:35][CH2:36][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=4)[CH2:10]3)[CH2:32][CH2:33][C:27]=2[CH:26]=1
Reactant: COc1cc2c(cc1OC)CC(NCc1ccccc1)CC2
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(Cc1ccccc1)C1CCc3cc(OC)c(OC)cc3C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 2-benzylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene with 1-(7,8-dimethoxy-1,3,4,5-tetra hydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane. IR spectrum (methylene chloride): 1645 cm-1 (C=O).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[NH2:12].[OH-].[K+].Cl>CO>[NH2:12][C:5]1[C:6]([Cl:11])=[CH:7][C:8]([I:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(I)cc(Cl)c1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(Cl)cc(I)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of 526 mg (1.69 mmol) of 2-amino-3-chloro-5-iodo-benzoic acid methyl ester in 9.0 mL methanol was added 474 mg of potassium hydroxide (8.44 mmol). The solution was stirred at room temperature for 18 hours. An additional 474 mg (8.44 mmol) of potassium hydroxide was added and the solution was heated in an oil bath at 45° C. for 4.5 hours. The solution was acidified to pH=3 by a dropwise addition of 1N aqueous hydrochloric acid. The resulting precipitate was collected by vacuum filtration. The solid was dissolved in methanol and concentrated to dryness. Acetone was added to the residue and the insoluble white precipitates were filtered off. The filtrate was concentrated to afford 500 mg (1.68 mmol, quantitative yield) of 2-amino-3-chloro-5-iodo-benzoic acid as a brown powder. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.76 (d, 1H), 6.91 (s, br., 2H); MS: m/z 295.8 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([OH:17])[CH2:14][NH:15][CH3:16])[CH2:8][CH2:7]1.[O:22]=[C:23]1[NH:27][C:26]([C:28]([F:31])([F:30])[F:29])=[C:25]([C:32]([OH:34])=O)[S:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C@H:13]([OH:17])[CH2:14][N:15]([CH3:16])[C:32]([C:25]2[S:24][C:23](=[O:22])[NH:27][C:26]=2[C:28]([F:29])([F:30])[F:31])=[O:34])[CH2:10][CH2:11]1
Reactant: CNC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1sc(=O)[nH]c1C(F)(F)F
Product: CN(C[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)C(=O)c1sc(=O)[nH]c1C(F)(F)F
Yield: 35.7 %

Procedure:
Prepared as Example 1 using (2R)-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-(methylamino)propan-2-ol (150mg, 0.45 mmol) and 2-oxo-4-(trifluoromethyl)-2,3-dihydro-1,3-thiazole-5-carboxylic acid (0.096 g) to yield the title compound as a colourless solid (0.085 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[C:8]1[CH3:23])(=[O:3])[CH3:2]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[C:8]1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCn1c(C)cc(C(=O)OCc2ccccc2)c1C
Solvent: CCO
Product: CC(=O)NCCn1c(C)cc(C(=O)O)c1C

Procedure:
2.4 g (7.6 mmol) of benzyl 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole-3-carboxylate from Example 3 are dissolved in 200 ml of ethanol and hydrogenated in the presence of 0.5 g of 10% strength Pd-on-charcoal at room temperature. After the mixture has been concentrated, the resulting solid is stirred with methylene chloride and filtered off with suction.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(OC)ccc(-c3cccc4c3CCC4=O)c2OC)COC1
Temperature: 80 °C
Yield: 17.9 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (155 mg, 1.124 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (82 mg, 0.422 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 17.9%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:7]=1[C:8](O)=[O:9].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[CH2:38][OH:39])=[CH:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:7]=1[C:8]([O:39][CH2:38]/[CH:37]=[CH:36]/[C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:25]2[NH:24][CH:28]=[CH:27][N:26]=2)=[CH:31][CH:32]=1)=[O:9]
Reactant: OC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
356 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2,3-dichlorophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexyl-carbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylamino-pyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 481 mg (87%).