Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([N:17]1[C:21]([N:22]2[N:31]=[C:30]3[C:24]([CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][C:29]=43)=[CH:23]2)=[N:20][CH:19]=[N:18]1)([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:36]([C:33]2[CH:34]=[CH:35][C:28]3[O:27][CH2:26][CH2:25][C:24]4[C:30](=[N:31][N:22]([C:21]5[N:17]([CH:14]([CH3:15])[CH3:16])[N:18]=[CH:19][N:20]=5)[CH:23]=4)[C:29]=3[CH:32]=2)=[O:37])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
A mixture of N-Boc piperazine (101 mg, 0.54 mmol), 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carboxylic acid (180 mg, 0.53 mmol), EDCI (151 mg, 0.79 mmol), HOBt (107 mg, 0.795 mmol) and triethylamine (216 L, 1.54 mmol) in DMF (2 mL) was stirred at RT for 20 h. The mixture was diluted with ethyl acetate and washed (water, saturated aqueous sodium hydrogen carbonate and then brine), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene-9-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (258 mg, 96%). The intermediate carboxylic acid tert-butyl ester was dissolved in DCM (20 mL) and treated with 4N HCl in dioxane (4 mL) and stirred for 3 h at RT before adding diethyl ether (20 mL). The resultant precipitate was collected by filtration and washed with diethyl ether to give 145 as a white solid (209 mg, 93%). 1H NMR (400 MHz, DMSO-d): δ 9.32 (s, 2 H); 8.37 (s, 1 H); 8.31 (d, J=2.20 Hz, 1 H); 8.06 (s, 1 H); 7.44 (dd, J=8.37, 2.21 Hz, 1 H); 7.15 (d, J=8.37 Hz, 1 H); 5.32-5.23 (m, 1 H); 4.37 (t, J=4.98 Hz, 2 H); 3.77 (s, 4 H); 3.15 (t, J=6.94 Hz, 6 H); 1.51 (d, J=6.59 Hz, 6 H). LCMS: RT=6.02 min, M+H+=408
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:30])[CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:15][CH2:14]4)=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O1CCOCC1>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[CH2:21][C:20]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)[CH:9]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (180 mg, 0.306 mmol) was added HCl (4 mL, 16.00 mmol) 4M in dioxane. The reaction was let stir at room temp overnight. The reaction was concentrated then diluted with diethyl ether and filtered to isolate 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (140 mg, 0.249 mmol, 82% yield) as a light yellow solid as the dihydrochloride salt. LC/MS (ES) m/z=489.0 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ 8.39 (s, 1H), 8.24 (d, J=8.34 Hz, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.32-7.37 (m, 1H), 7.04-7.20 (m, 3H), 5.08-5.18 (m, 1H), 4.36 (t, J=8.46 Hz, 2H), 3.99 (s, 2H), 3.68 (s, 3H), 3.65 (d, J=13.89 Hz, 2H), 3.36-3.40 (m, 2H), 2.41-2.53 (m, 2H), 2.37 (d, 2H).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=O)=[CH:10][CH:9]=2)[O:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4]1.C(N(S(F)(F)[F:29])CC)C>ClCCl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:16][F:29])=[CH:10][CH:9]=2)[O:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CS(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Solvent: ClCCl
Product: FCSc1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 20 (390.9 g, 1.11 mol) and SbCl3 (7.62 g, 0.0334 mol) in anhydrous dichloromethane (2.27 L) at −15° C., diethylamino sulfurtrifluoride (DAST) (258 ml, 2.0 mol) was added drop-wise. The reaction mixture was stirred for 3 hours at −20° C. and then allowed to warm up to room temperature overnight. The reaction was quenched with 1N NaOH solution until pH=3-4 at −20° C., and then solid NaHCO3 was added to pH=8. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to provide 330 g of the desired product as a brown oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([S:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: Fc1ccc(CS)cc1
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(SCc2ccc(F)cc2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsilanyl)ethoxy]methyl}benzenesulphonamide (Example 55a) (0.4 g) and (4-fluorophenyl)methanethiol (0.13 g). The intermediate product containing the SEM group was purified by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.2 g
Reaction SMILES: [C:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CCO.[Pd]>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(C2=CCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(C2CCCC2)cc1
Yield: 93.7 %

Procedure:
A solution of 4-cyclopent-1-enyl-benzoic acid (2.6 g, 13.8 mmol) in EtOH (20 mL) is hydrogenated with 10% Pd/C (0.25 g) at 20 psi H2 for 2 h. It is filtered through Celite® and concentrated to give 2.46 g (95%) of the title compound. LC/MS (m/z): calcd for C12H14O2 (M−H)−: 189.2; found: 189.2.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]([CH:12]([C:17]1[S:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][N:21]=1)[CH2:13][CH2:14][CH2:15]I)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:4][CH:12]([C:17]1[S:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][N:21]=1)[CH2:13][CH2:14][CH2:15][N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: CC(C)(C)[Si](C)(C)OC(CCCI)c1ncc(S(N)(=O)=O)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)CCCC(O)c1ncc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Dimethylamine was bubbled through a solution of 2-(1-t-butyldimethylsiloxy-4-iodobutyl)-5-thiazole sulfonamide (0.78 mmol, 0.37 g ) in THF (8 mL) at 0° C. After 30 minutes the solvent was removed and the residue taken up in THF and TBAF (1.17 mmol) added. The reaction was stirred at rt for 2 hours. The reaction was concentrated and the residue subjected to flash chromatography (5% MeOH/NH3 /CHCl3) to afford 0.16 g (72%) of 2-(1-hydroxy-4-(N,N-dimethylamino)butyl)-5-thiazole sulfonamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[S:10](=[O:13])([OH:12])[O-:11].[Na+:14]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10]([O-:13])(=[O:12])=[O:11].[Na+:14]
Reactant: O=S([O-])O
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
A solution of 5 g indole in 10 mL ethanol was added to a solution of 8.8 g sodium bisulfite in 30 mL water. The mixture was stirred at room temperature for 12 hrs. The solid precipitate was filtered, washed with ether, and dried to yield sodium indole-2-sulfonate (7.8 g, 91%) as a white solid. The product was used in the next step without further purification. MP>320° C.; IR (KBr, cm−1) 3470, 3250, 1650, 1600, 1490, 1460, 1210, 1170, 1040, 760, 750.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:6]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16]([N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:11][CH:12]=2)[N:6]=1
Reactant: CCCCNCCCC
Reactant: Nc1nc(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)cs1
Solvent: CS(C)=O
Product: CCCCN(CCCC)C(=O)NCCc1ccc(-c2csc(N)n2)cc1

Procedure:
The title compound: A solution of phenyl N-{2-{4-(amino-4-thiazolyl)phenyl}ethyl}carbamate (200 mg, 0.59 mmol), prepared in the preceding section (a), and dibutylamine (76.0 mg, 0.59 mmol) in DMSO (1 mL) was stirred at room temperature for 3 d. The reaction mixture was diluted with EtOAc (30 mL) and washed with aqueous saturated NaHCO3 (2×30 mL). The aqueous layers were back extracted with EtOAc (30 mL). The combined organic extracts were dried (MgSO4) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc:Hexane, 4:1) to give N-{2-{4-(2-amino-4-thiazolyl)phenyl}ethyl}-N',N'-dibutylurea (167 mg, 76% yield): M.p. 42-43°; 1H NMR (DMSO-d6) δ 7.70 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 6.99 (broad s, 2H), 6.92 (s, 1H), 6.11 (broad t, J=5.4 Hz, 1H), 3.23 (broad q, J=6.6 Hz, 2H), 3.09 (t, J=7.5 Hz, 4H), 2.70 (t, J=7.3 Hz, 2H), 1.37 (m, 4H), 1.21 (m, 4H), 0.86 (t, J=7.3 Hz, 6H); MS (FAB) m/z 375 (MH)+.
Reaction SMILES: C(OC(NC1CCCC(C(O)=O)C1)=O)C1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.NC1C(=O)N(CC2C=CC=CC=2)C=CC=1N.CCN=C=NCCCN(C)C.[CH2:58]([O:65][C:66](=[O:92])[NH:67][CH:68]1[CH2:73][CH2:72][CH2:71][CH:70]([C:74](=O)[NH:75][C:76]2[C:77](=[O:90])[N:78]([CH2:83][C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[CH:79]=[CH:80][C:81]=2[NH2:82])[CH2:69]1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.C(O)(=O)C>CN(C=O)C.O>[CH2:58]([O:65][C:66](=[O:92])[NH:67][CH:68]1[CH2:73][CH2:72][CH2:71][CH:70]([C:74]2[NH:75][C:76]3[C:77](=[O:90])[N:78]([CH2:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[CH:79]=[CH:80][C:81]=3[N:82]=2)[CH2:69]1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: Nc1ccn(Cc2ccccc2)c(=O)c1NC(=O)C1CCCC(NC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccn(Cc2ccccc2)c(=O)c1N
Agent: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(NC1CCCC(c2nc3ccn(Cc4ccccc4)c(=O)c3[nH]2)C1)OCc1ccccc1
Temperature: 0 °C
Yield: 45.6 %

Procedure:
3-Benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.52 g, 1.86 mmol), TEA (0.41 g, 4.09 mmol), and HOBt (0.50 g, 3.72 mmol) were added sequentially to a solution of 3,4-diamino-1-benzyl-1H-pyridin-2-one (0.40 g, 1.86 mmol) in DMF (15 mL) at room temp. After the solution was cooled to 0° C., EDCI (0.71 g, 3.72 mmol) was added and the resulting solution was allowed to stir, with warming to room temp, for 17 h. The reaction mixture was diluted with water (10 mL) extracted with CH2Cl2, dried with MgSO4, and concentrated. The crude [3-(4-amino-1-benzyl-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester (0.57 g, 1.20 mmol) was dissolved in glacial acetic acid (7.21 g, 120.1 mmol), and heated at 120° C. for 2 days. After cooling to room temperature, the solvent was evaporated under reduced pressure and the cyclized product was purified by flash chromatography, eluting with 3% MeOH in CH2Cl2 to give [3-(5-benzyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.25 g, 30% for 2 steps). 1H-NMR (DMSO): δ 7.46 (m, 1H), 7.25–7.38 (m, 10H), 6.57 (m, 1H), 5.20 (s, 2H), 5.01 (s, 2H), 3.41 (m, 1H), 2.89 (m, 1H), 2.13 (m, 1H), 1.80 (m, 3H), 1.42 (m, 2H), 1.21 (m, 2H). MS: calculated for C27H28N4O3+H 457.2; found: 457.5.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[C:9]1[CH3:22].[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH3:22]
Reactant: CC1=CN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Agent: [S]
Product: CC1=C(c2ccncc2C)SCC(=O)N1
Yield: 85.2 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (0.25 g) and sulfur sublimed (0.125 g) was treated in the same manner as described in Example 3 (ii) to give the titled compound (0.118 g, yield 86.3%) as pale brown crystals. Chloroform-methanol (=20:1) was used as a developing eluant.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=O)[CH3:2].[C:25]([NH:33][NH2:34])(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>C1(C)C(C)=CC=CC=1>[CH:20]1([C:5]2[C:6]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[N:7][N:8]3[C:4]=2[C:1]([CH3:2])=[N:34][N:33]=[C:25]3[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C1CCCC1
Reactant: NNC(=O)c1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Temperature: 180 °C

Procedure:
Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-yl ester (0.65 g, 1.87 mmol) and benzhydrazide (0.28 g, 1.1 molar eq) were stirred together in xylene (20 ml) at reflux for 2.5 h. The solvent was reduced to ˜5 ml and Dowtherm A (20 ml) was added and the reaction mixture was heated at 180° C. for 2 h. The mixture was cooled and poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-6% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a light brown solid (0.62 g). 1H NMR (360 MHz, CDCl3) δ 1.73-2.07 (8H, m), 2.49 (3H, s), 2.91 (3H, s), 3.48 (1H, m), 7.26-7.61 (5H, m), 7.93-7.97 (2H, m), 8.13-8.15 (2H, d, J=8.7 Hz); MS (ES+) m/e 449 [MH]+.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].N12CCCN=C1CCCCC2.[CH2:17]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[C:27]=2[CH3:30])[C:22]1=[O:33])[CH2:18][CH2:19][CH3:20]>O1CCCC1.CCOCC>[CH2:17]([C:21]1([CH2:2][CH2:1][C:3](=[O:4])[CH3:5])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[C:27]=2[CH3:30])[C:22]1=[O:33])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1Cc2c(ccc(OC)c2C)C1=O
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC1(CCC(C)=O)Cc2c(ccc(OC)c2C)C1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 81.4 %

Procedure:
Methyl vinyl ketone (MVK, 0.49 mL, 5.9 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 0.8 mmol) were added to a solution of impure 2-butyl-5-methoxy-4-methyl-1-indanone (0.90 g, 3.9 mmol) in anhydrous tetrahydrofuran (THF, 3.9 mL). The resulting solution was stirred at room temperature for 30 hours, then diluted with Et2O (50 mL), washed with water (20 mL), 1N HCl (20 mL), and brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum to an amber oil (1.23 g). The crude product was purified by chromatography on EM silica gel 60 (230-400 mesh, 125 mL dry, packed under 4:1 hexanes-EtOAc). The column was eluted with 4:1 hexanes-EtOAc, collecting 25 mL fractions. Fractions 14-27 gave a 93:2:5 mixture (0.96 g) of 2-butyl-5-methoxy-4-methyl-2-(3-oxo-butyl)-1-indanone, the 6-methyl isomer, and the desmethyl product. This material was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([C:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:39])[F:38])[CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)(=[O:15])=[O:16])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:38])[F:39])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of (R)-tert-butyl 4-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (620 mg, 1.06 mmol) in MeOH (50 mL) was added Pd/C (˜100 mg). The mixture was purged with nitrogen and then stirred under H2 balloon at room temperature for 2 h. The reaction mixture was filtered through Celite and concentrated. The crude product was purified by SiO2 gel column eluted with hexanes/EtOAc to give the titled compound as a light yellow solid (569 mg, 92%). HRMS: calcd for C28H35F4N3O4S+H+, 586.23572. found (ESI-FTMS, [M+H]1+), 586.23585.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39](O)=[O:40])[CH:37]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][N:20]([C:39]([C:38]5[CH:37]=[C:36]([CH:44]=[CH:43][CH:42]=5)[C:35]([O:34][CH3:33])=[O:45])=[O:40])[CH2:21][CH2:22]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole IIa (300 mg, 0.7 mmol) in dichloromethane (10 mL) was added isophthalic acid monomethyl ester (138.9 mg, 0.77 mmol) and triethyl amine (107 μL, 0.77 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (146.7 mg, 0.77 mmol) and 4-dimethylaminopyridine (8.5 mg. 0.07 mmole). After being stirred for 4 hours at ambient temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3×40 mL). The combined organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate 10 as amorphous solid (297 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.13-8.08 (m, 2H), 7.70 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.45-7.40 (m, 2H), 7.35-7.30 (m, 4H), 7.20-7.15 (m, 2H), 4.68 (br, 1H), 4.2 (br, 1H), 3.96 (s, 3H), 3.57 (br, 1H), 3.43-4.31 (m, 4H), 2.60 (s, 3H), 2.42 (br, 3H), 2.19 (br, 1H), 1.99-1.92 (m, 10H), 1.69 (br, 2H). HRMS m/z (M+H)+ calcd 591.33335; obsd 591.3325.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[O:12][C:13]2[C:14](=[C:16]([S:22](Cl)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH:15]=1)(=[O:10])[CH3:9].[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>ClCCl>[C:8]([C:11]1[O:12][C:13]2[C:14](=[C:16]([S:22]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH:15]=1)(=[O:10])[CH3:9]
Reactant: NCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NCc2cccnc2)c2cc(C(C)=O)oc12

Procedure:
Triethylamine (0.43 ml) was added to a solution of 2-acetyl-7-methoxy-4-benzofuransulphonyl chloride (600 mg) and 3-(aminomethyl)pyridine (0.25 ml) in dichloromethane at room temperature. The resultant mixture was stirred for 20 hours and then diluted with dichloromethane (20 ml). The solution was washed with water (20 ml) and brine (20 ml) and dried (MgSO4). Concentration in vacuo provided a dark oil which was applied to a silica column and eluted with 2% methanol in dichloromethane. The title compound was obtained as a pale yellow solid (161 mg). Mp 168°-170° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH2:12])=O)=[CH:6][C:5]=12.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:12])=[CH:6][C:5]=12
Reactant: NC(=O)c1ccn2ccnc2c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccn2ccnc2c1
Yield: 93.1 %

Procedure:
To a solution of Imidazo[1,2-a]pyridine-7-carboxylic acid amide (38 mg, 0.24 mmol) and triethylamine (0.066 ml, 0.47 mmol) in CH2Cl2 (5 ml) was added trifluoroacetic anhydride (0.39, 2.83 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 h before the crude mixture was loaded onto a SCX SPE cartridge, washing with MeOH and eluting with the product with 2M NH3/MeOH. Removal of solvent in vacuo afforded the title compounds (32 mg). MS: [M+H]+143.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=O)[NH:14][N:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([N:8]1[C:12]2=[C:13]([Cl:21])[N:14]=[N:15][CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2cn[nH]c(=O)c2n1Cc1ccccc1
Product: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Temperature: 85 °C
Reaction time: 7 h
Yield: 84 %

Procedure:
A suspension of 2.0 g (8.3 mmol) of 1-benzyl-2-methyl-6,7-dihydropyrrolo[2,3-d]pyridazine 7-one in 20 ml of phosphorus oxychloride is stirred at 85° C. for 7 h. The excess phosphorus oxychloride is subsequently distilled off and the residue is hydrolyzed in 50 ml of water. After neutralization with 2 N sodium hydroxide solution, the mixture is extracted with 3×50 ml of dichloromethane. The organic extracts are washed with 50 ml of water, dried over magnesium sulfate and concentrated. The residue is recrystallized from methanol. 1.8 g (84%) of the title compound are isolated. M.p.: 152°-156° C.