Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:40][CH2:41][Cl:42])(=[O:39])[CH2:37][CH3:38]>C(#N)C>[Cl-:42].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:21][CH:22]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:41][O:40][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCC(=O)OCCl
Solvent: CC#N
Product: CCC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4ccnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 12 h
Yield: 10.9 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (0.80 g) and chloromethyl propanate (4.07 g) was added acetonitrile (1.6 ml), and the mixture was stirred for 12 hours at 100° C. under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and to the residue was added diisopropyl ether (8 ml). The resulting powder was collected by filtration. The powder was subjected to silica gel flush chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=9/1→4/1), and a fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo, and the residue was dissolved in water (10 ml). The solution was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-propanoyloxymethyl-1H-1,2,4-triazolium chloride (Compound 13, 0.11 g) as a white powder.
Reaction SMILES: Cl.[C:2](=[NH:12])([O:9]CC)[C:3]1[CH:8]=[CH:7]C=CC=1.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH2:21]CC.[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:20]([O:24][C:26]1([CH:31]=[CH:30][CH:29]=[CH:28][CH2:27]1)[CH:32]=[N:12][C:2](=[O:9])[CH2:3][CH2:8][CH3:7])[CH3:21]
Reactant: CCCC(=O)Cl
Reactant: Cc1ccccc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N=CC1(OCC)C=CC=CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
First, 10 g of ethyl benzimidate hydrochloride, 150 mL of toluene, and 11 g of triethylamine (Et3N) were put into a 500-mL three-neck flask and this mixture was stirred at room temperature for 10 minutes. After a predetermined time elapsed, with a 50-mL dropping funnel, a mixed solution of 5.8 g of butyryl chloride and 30 mL of toluene was added dropwise to this mixture, and the mixture was stirred at room temperature for 24 hours. After the stirring, this mixture was suction-filtered, and the obtained filtrate was concentrated to give N-(1-ethoxybenzylidene)butyramide (a yellow oily substance, 100% yield). The synthesis scheme of Step 1 is shown in (A-1) below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: CC[C@@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a solution of 60 mg of (S)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester in N,N-dimethylformamide (2.0 mL) is added 66 mg of 3-bromomethyl-4,6-dimethyl-1,2-benzoisothiazole and 36 mg potassium carbonate at room temperature. The mixture is heated to 60° C. for 2.5 h. Then 50 mL of water is added and the product is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel to give 80 mg (82%) of (S)-3-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][C:43]4=[O:48])=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:50].O1CCOCC1>C(Cl)Cl>[ClH:50].[ClH:50].[ClH:50].[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:37]=[CH:38][C:39]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][C:43]4=[O:48])=[CH:40][CH:41]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N5CCCCC5=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccc(N5CCCCC5=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.1 %

Procedure:
tert-Butyl[1-(4-{2-[4-(2-oxopiperidin-1-yl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (31.9 mg, 0.0489 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 19 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (27.2 mg, 84.1%) as yellow solid. 1HNMR (DMSO-d6) 500 MHz δ: 8.80-8.69 (m, 3H), 8.65 (br s, 1H), 8.13-8.09 (m, 1H), 7.98-7.93 (m, 1H), 7.59-7.54 (m, 2H), 7.51-7.47 (m, 2H), 7.41-7.29 (m, 4H), 7.25-7.21 (m, 2H), 7.16-7.11 (m, 1H), 6.93-6.88 (m, 1H), 6.75 (dd, J=7.7, 4.9 Hz, 1H), 3.62-3.57 (m, 2H), 2.62-2.47 (m, 4H), 2.41-2.35 (m, 2H), 2.24-2.13 (m, 1H), 1.90-1.78 (m, 5H); LCMS: 553 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1.[F:8][C:9]1[C:19]([N:20]2[C:28](=[O:29])[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]2=[O:30])=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:8][C:9]1[C:19]([N:20]2[C:28](=[O:29])[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]2=[O:30])=[CH:18][C:12]2[N:13]([CH2:2][C:3]3[CH:7]=[CH:6][O:5][N:4]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: ClCc1ccon1
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1Cc1ccon1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A compound of 3-(chloromethyl)-isoxazole (1.2 g) was added dropwise at a temperature of 20° to 30° C. under stirring to a mixture of 7-fluoro-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (3.16 g), acetonitrile (50 ml) and potassium carbonate (1.5 g). The reaction mixture was heated under refluxing for 3 hours, cooled to room temperature, and filtered. The filtrate was concentrated under a reduced pressure to dryness. The resultant residue was mixed with toluene (150 ml) to form a suspension, which was then filtered to remove the undissolved materials therefrom. The filtrate was concentrated under a reduced pressure so as to obtain a viscous material, which was thereafter dissolved in a minimum amount of ethanol. The ethanol solution was cooled to precipitate a crystalline product. This product was separated by filtration and dried, so that the aimed compound, i.e. 7-fluoro-4-(isoxazol-3-ylmethyl)-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (3.3 g) was obtained. m.p. 206°-210° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH2:10])[CH:2]=[CH2:3].[CH3:11][NH:12][S:13]([C:16]1[CH:17]=[C:18]([C:26](Cl)=[O:27])[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1)(=[O:15])=[O:14]>>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:26]([C:18]1[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=[C:16]([S:13](=[O:15])(=[O:14])[NH:12][CH3:11])[CH:17]=1)=[O:27])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: C=CCN1CCCC1CN
Product: C=CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 52.6 %

Procedure:
In a similar manner to the above example, 84 g of dextrorotatory 1-allyl-2-aminomethyl-pyrrolidine was reacted with 175 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give, after purification, 125 g of dextrorotatory-N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 104°-105° C.; yield: 52.6%).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1.Cl[CH2:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>O.CN(C)C=O>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[CH2:17][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1
Reactant: COC(=O)Nc1ccc(O)cc1C
Reactant: ClCc1nc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A solution of 3.6 g of potassium hydroxide in 10 ml of water was added to a solution of 10.0 g of methyl N-(4-hydroxy-2-methylphenyl)carbamate [prepared as described in Example 15(a) above] in 30 ml of dimethylformamide and 6 ml of water cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 20 minutes, and then a solution of 10.0 g of 2-chloromethylbenzothiazole in 25 ml of dimethylformamide was added to the reaction mixture. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 1 hour, at the end of which time the temperature was elevated further to 60° C. and the reaction mixture stirred for a further 2 hours. The reaction mixture was then poured into water to give a crystalline precipitate which was washed with water and further washed with diethyl ether and then recrystallised from ethyl acetate to give 10.5 g (yield 59%) of the title compound as a crystalline solid having a melting point of 147° to 149° C. The proton nuclear magnetic resonance spectrum was identical to that for the title compound of Example 21.
Reaction SMILES: [CH2:1]([CH2:11]/[C:12](/[CH3:21])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:22]([O:19][CH2:18][CH:17]=[C:16]([CH3:20])[CH2:15][CH2:14][CH:13]=[C:12]([CH3:21])[CH2:11][CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:23])[CH2:37][CH2:36]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)N1CCN(C)CC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of alcohol 1 (160 mg, 55 mmol) in DCM (3 mL) at 0° C. was added carbonyldiimidazole (CDI) (107 mg, 0.66 mmol) and the reaction was stirred for 1 h. Then N-methylpiperazine (80 mg, 0.72 mmol) and DMAP (68 mg, 0.55 mmol) were added and stirred for 12 h. Solvent was removed and the residue was purified by column chromatography (DCM/MeOH) to give the carbamate 40a as a viscous oil in 88% yield (191 mg). TLC Rf: 0.54 (10% MeOH/DCM); 1H NMR (300 MHz, CDCl3): δ 5.34 (t, 3H), 5.08 (m, 3H), 4.59 (d, 2H), 3.49 (m, 4H), 2.35 (m, 4H), 2.29 (s, 3H), 2.10-1.97 (m, 12H), 1.70 (s, 3H), 1.67 (s, 3H), 1.59 (s, 9H); LCMS: MS (m/z): 417 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.CCN(CC)CC.[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>C(Cl)Cl>[CH3:22][CH:21]([CH3:23])[CH2:20][C:19]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)=[O:24]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C(=O)CC(C)C)C1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Ethyl (S)-Piperidine-3-carboxylate (25 g, 159.02 mmol) in anhydrous DCM (500 mL) was cooled down to 0° C. and treated with Et3N. A solution of isovaleryl chloride (23.27 mL, 190.08 mmol, 1.2 eq.) in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting reaction mixture was kept on the cooling bath and allowed to warm up slowly to room temperature. After 6 hrs the reaction was washed subsequently with aqueous HCl solution (2M), saturated NaHCO3, brine, dried over Na2SO4, filtered, concentrated under vacuum and purified by filtration over a short silica gel column using EtOAc as solvent. The solvent was removed under vacuum to yield the desired product as pale yellow oil (37.4 g, 154.97 mmol, 97.5%) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 20° C.) δ 0.88 (pseudo d, J=6.4 Hz, 6H), 1.13-1.23 (m, 3H), 1.26-1.45 (m, 1H), 1.47-1.75 (m, 2H), 1.82-2.03 (m, 2H), 2.10-2.28 (m, 2H), 2.28-2.39 (m, 0.5H), 2.45-2.56 (m, 0.5H), 2.84 (dd, J=10.0, 12.8 Hz, 0.5H), 2.97-3.11 (m, 1H), 3.38 (dd, J=8.8, 13.6 Hz, 0.5H), 3.63-3.83 (m, 1.5H), 4.00-4.14 (m, 2H), 4.26-4.36 (dm, 0.5H). MS 242 (MH).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl.O>[C:34](=[O:35])([O:36][CH2:37][CH3:38])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:5]=4[C:6]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) (1.0 equiv.) and triethyl amine (2 equiv.) in dichloromethane (0.10 M) at 0° C. was added ethyl chloroformate (1.2 equiv.). The resulting mixture was allowed to stir for 30 minutes at 0° C., after which it was diluted with water and dichloromethane. The biphasic layers were separated and the aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexanes to provide 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl ethyl carbonate as a solid. 1H NMR (Acetone-d6): δ 8.78 (s, 1H), 8.73 (s, 1H), 8.28 (d, 1H), 7.43 (s, 1H), 7.33 (d, 2H), 7.10-7.17 (m, 3H), 6.64 (br, 2H), 4.18 (t, 2H), 3.25 (t, 2H), 3.14 (t, 2H), 2.45 (s, 3H), 1.68-1.77 (m, 2H), 0.97 (t, 3H). LRMS [M+H]=416.2
Reaction SMILES: IC.[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23](=[S:26])[NH:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1.[CH2:27](N(CC)CC)C>CCO>[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23]([S:26][CH3:27])=[N:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1
Reactant: CCN(CC)CC
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3n[nH]c(=S)o3)cc12)C1CC1
Solvent: CI
Solvent: CCO
Product: CSc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Iodomethane (0.069 ml, 1.111 mmol) was added in one portion to a stirred solution of (R)-4-(1-cyclopropylethylamino)-6-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 126, 306 mg, 0.889 mmol) and triethylamine (0.310 ml, 2.221 mmol) in absolute EtOH (3.55 ml). The reaction mixture was allowed to stir at rt for 2 hrs before evaporating in vacuo. The residue was then partitioned between 1N HCl and ethyl acetate. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was treated with MeOH and the solid filtered to give the title compound (135 mg, 0.377 mmol, 42.4% yield) as a white solid. The filtrate (which contained the remainder of the product) was evaporated and retained. HPLC (condition B): retention time=3.98 min. LCMS (condition B): MH+ m/z 358.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.88 (1 H, d, J=8.32 Hz), 8.31 (1 H, s), 8.27 (1 H, d, J=1.66 Hz), 7.32 (1 H, d, J=1.94 Hz), 3.89-4.04 (1 H, m), 3.30 (3 H, s), 1.34 (3 H, d, J=6.38 Hz), 1.01-1.20 (1 H, m), 0.44-0.58 (2 H, m), 0.35-0.44 (1 H, m), 0.20-0.35 (1 H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=[CH:9][C:10]1[C:11]([CH:16]2[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:5][C:6]([OH:8])=O.[C:20]([O-])(=[O:22])[CH3:21].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:10]2[C:15]([CH:14]=[CH:13][N:12]=[C:11]2[CH:16]2[CH2:18][CH2:17]2)=[C:6]([O:8][C:20](=[O:22])[CH3:21])[CH:5]=1)=[O:19]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(=Cc1cccnc1C1CC1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC(C)=O)c2ccnc(C3CC3)c2c1
Temperature: 155 °C

Procedure:
2-[1-(2-Cyclopropyl-pyridin-3-yl)-methylidene]-succinic acid 1-methyl ester (18.9 g, 72.4 mmol), sodium acetate (5.94 g, 72.4 mmol) was suspended in AcOH (150 ml) and heated at 155° C. for 6 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 6/4) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[O:14][CH2:15][C:16](=[O:23])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH3:24])[CH:7]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCCCC1>C(O)C>[CH:18]([OH:20])=[O:19].[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28]([CH:35]=[C:15]2[O:14][C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:25])=[CH:7][C:8]=3[CH3:24])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:27]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(NCCN(C)C)cc2C)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(NCCN(C)C)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Product: O=CO
Temperature: 25 °C
Yield: 8.2 %

Procedure:
To a solution of ethyl 2-[(4-{[2-(dimethylamino)ethyl]amino}-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.27 g, 0.70 mmol) which similarly prepared according to the procedure described in the Example 125, First step to Third step and 7-azaindole-3-carboxaldehyde (0.11 g, 0.70 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the solvent was removed under reduced pressure then the residue was purified by preparative HPLC to afford the titled compound as solid (0.015 g, y. 8%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[ClH:36].[C:27]1([S:33]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]4[CH:24]5[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]5)[CH2:20]4)=[O:18])=[CH:14][CH:15]=3)=[CH:6][CH:5]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2

Procedure:
A solution of 80 mg (0.20 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 71.7 mg (0.41 mmol) of phenylsulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 52 mg (51.5%0 of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21]S(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]1[O:30][C:29]2[CH:31]=[C:32](O)[CH:33]=[CH:34][C:28]=2[O:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[O:27]1[C:28]2[CH:34]=[CH:33][C:32]([O:21][CH2:20][CH:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12]([C:8]4([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)[CH2:11][CH2:10][CH2:9]4)=[O:13])[CH2:15]3)=[CH:31][C:29]=2[O:30][CH2:26]1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 43 (1.0 g, 2.59 mmol) in acetonitrile (25 mL) was added sesamol (0.36 g, 2.59 mmol) and cesium carbonate (1.27 g, 3.89 mmol). The reaction was stirred and refluxed for 20 h. After cooling to room temperature, the reaction mixture was filtered and most of the solvent was removed by rotary evaporation. The residue was partitioned between dichloromethane and water, and the organic layer was washed with sat. sodium carbonate (2×50 mL) and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol (98:2) to give 0.68 g of the amide 44 as a crystalline solid. C24H26ClNO4, MS (m/z)=428 (MH+).