Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][OH:18])[CH3:13]>>[CH2:12]([N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][O:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCN(CC)CCCO
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1F

Procedure:
In a manner similar to that described in Example 231 a, 3,4-difluoronitrobenzene (6.7 mL, 60.6 mmol, 1 equiv.) and 3-diethylamino-1-propanol (9 mL, 1 equiv.) are converted to the named compound as a brown oil (16.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][CH2:19][C:9]2=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([CH3:18])=[C:8]2[CH2:7]1)=[O:5])[CH3:2].[OH:22]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][CH2:19][C:9]2=[N+:10]([O-:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([CH3:18])=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCc2nc3ccccc3c(C)c2C1
Reactant: OO
Product: CCOC(=O)N1CCCc2c(c(C)c3ccccc3[n+]2[O-])C1
Yield: 60 %

Procedure:
2,3,4,5-Tetrahydro-11-methyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester 6-oxide was prepared analogous to Example 111 from 2,3,4,5-tetrahydro-11-methyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:14][CH2:13][CH:12]([N:8]1[C:6]2=[N:7][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[OH:11])[CH2:15][CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)n1c(O)nc2ncc(C#C[Si](C)(C)C)nc21
Temperature: 80 °C
Yield: 80.2 %

Procedure:
A mixture of 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (3.75 g, 13.2 mmol)), trimethylsilylacetylene (2.8 mL, 19.8 mmol), PdCl2(PPh)2 (0.93 g, 1.32 mmol), CuI (0.5 g, 2.64 mmol) and triethylamine (5.5 mL, 39.5 mmol) in DMF (50 mL) was purged with N2 for 30 seconds followed by stirring at 80° C. After 3 hours the reaction mixture was diluted with EtOAc, washed with NH4Cl solution, dried over Na2SO4, and concentrated in vacuo. Purification with over silica gel (Biotage MPLC 10-80% EtOAc/hexanes) provided the title compound (3.2 g, 80%) as a brown solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (1.70 g, 4.29 mmol) and triethylamine (2.40 mL, 17.2 mmol) in methylene chloride (8–10 mL) at 0° C. was added cyclohexanecarbonyl chloride (1.72 mL, 12.87 mmol) in methylene chloride (30 mL) dropwise. The reaction mixture was stirred for 1 hr. and was quenched with water/saturated sodium bicarbonate (1/1, 40–50 mL). The layers were separated and the aqueous solution was washed with methylene chloride (2×25 mL). The combined organic solutions were dried (magnesium sulfate), filtered, and concentrated. Medium pressure chromatography using a solvent gradient (methylene chloride to 10% methanol/methylene chloride) afforded the title compound of Step A. MS 507 (M+1)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>CN(C=O)C>[OH:1][CH2:2][CH2:3][S:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH:16][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCCO)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CNc2ncnc3c2ncn3[C@@H]2O[C@H](CSCCO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.9 %

Procedure:
A mixture of triol 1b (650 mg, 2.0 mmol), 4-nitrobenzyl bromide (2.16 g, 10 mmol), and powdered 4A molecular sieves (2.0 g) in dry DMF (15 mL was stirred for 4 days in a stoppered flask at ambient temperature, and filtered. The filtrate was concentrated under reduced pressure and the resulting crystalline mass was triturated with acetone (3×) and toluene (3×). The solid residue was dissolved in MeOH (10 mL) and treated with NH3 /MeOH (10 mL; w/v, 1:1, prepared at -10° C.). This solution was stirred for 5 h at ambient temperature and concentrated to a red gum. The gum was dissolved in hot MeOH and cooled to give a brown solid that was recrystallized from MeOH to give title compound 2 as red needles (360 mg, 39%). The mother liquors were concentrated and the residue subjected to flash chromatography (MeOH/CHCl3, 2:23) to give a red solid that was recrystallized to give further red needles (165 mg, 19%) of 2 (total 57%) with mp 157°-158° C.; UV (MeOH) max 270 nm (ε 24 700), HCl/MeOH) max 274 nm (ε 29 900), (NaOH/MeOH) max 271 nm (ε 24 500); IH NMR (Me2SO-d6) δ 8.62 (br s, 1, NH), 8.46 (s, 1, H8), 8.26 (s, 1, H2), 8.20 (d, JAB =8.8 Hz, 2, Ar), (d, 2, Ar), 5.96 (d, J1'-2' =5.7 Hz, 1, H1'), 5.56 (d, JOH-2' =5.8 Hz, 1, OH2'), 5.39 (d, JOH-3' =5.0 Hz, 1, OH3'), 4.85 (br s, 2, CH2Ar), 4.81 (t, J2'-3' =5.4 Hz, 1, H2' ), 4.18 (br q, J3'-4' =4.0 Hz, 1, H3'), 4.05 (m, J4'-5'a =6.0 Hz, J4'-5'b =7.2 Hz, 1, H4'), 3.54 (dt, J=5.5 Hz, 2, CH2OH2.97 (m, J5'a-5'b =13.8 Hz, 1, H5'a), 2.87 (m, 1, H5'b), 2.62 (t, 2, SCH2); 13C NMR (Me2SO-d6) δ 154.32 (C6), 152.56 (C2), 149.31 (Ar), 148.26 (C4), 146.35 (Ar), 140.13 (C8), 128.01 (Ar), 123.44 (Ar), 120.01 (C5), 87.44 (C1'), 84.04 (C4'), 72.71, 72.54 (C2',3'), 60.85 (CH2OH), 43.31 (CH2Ar), 34.63 (C5' ), 34.30 (SCH2); MS m/z 417.0969 [C17H17N6O5S (M-C2H5O)=417.0981]. Anal. Calcd for C19H22N6O6S (462.5): C, 49.34; H, 4.79; N, 18.17. Found: c, 48.99; H, 4.70; N, 18.04
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.O.C(=O)(O)[O-].[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCOCC1>[C:31]([N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NC(=O)C(Cc2ccc(OCCNc3ncccn3)cc2)S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A stirred solution of 5-[4-(2-(2-pyrimidinylamino)ethoxy)benzyl]-2,4-thiazolidinedione (800mg) in acetic anhydride (15 ml) and 1,4-dioxan (5 ml) was boiled under reflux for 3 hours. After cooling, the mixture was added to water (300 ml), neutralized (sodium bicarbonate) and extracted with dichloromethane (3×200 ml). The organic extracts were washed with brine (100 ml), dried (MgSO4), filtered and evaporated to dryness. Chromatography on silica-gel in dichloromethane of the residual oil afforded the title compound (m.p. 137° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: NCCCCN
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCCCN)nc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-pyridinecarbonitrile (5.0 g) was dissolved in 1,4-diaminobutane (50 ml), and the solution was stirred at 170° C. for 2 hours with heating. Diethyl ether and distilled water were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with diethyl ether. The aqueous layer was saturated with sodium chloride, and the resulting mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.77 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)ccc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)ccc2c1=O

Procedure:
Analogously to Example C, 7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is reacted with piperazine to give 1-cyclopropyl-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid which decomposes at 298°-300° C. Preparation Examples for the end products according to the invention:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][CH:24]=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][CH:24]=[CH:25][C:16]=12
Reactant: N#Cc1cnc2sccc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sccc23)c(Cl)cc1Cl
Yield: 21.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (300 mg, 1.57 mmol) and 60% sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes The solution is cooled and 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (150 mg, 0.8 mmol) [Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977)] is added. The reaction mixture is heated at reflux for 3.5 hours. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:3 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material is collected by filtration to provide 60 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 197-199° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.68 (d, J=5.7 Hz, 1H), 7.76 (s, 1H), 7.81 (d, J=5.7 Hz, 1H), 8.43 (s, 1H), 9.80 (s, 1H); MS 348.2 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]([C:7]([N:9]2[CH2:13][CH2:12][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH2:14][CH2:15]S(C)(=O)=O)[CH2:10]2)=[O:8])=[C:5]([O:30][C:31](=[O:33])[CH3:32])[C:4]=1[O:34][CH3:35])[CH3:2].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[C:50]([CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51])[CH3:37]>>[CH2:1]([C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]([C:7]([N:9]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:55]3[CH2:56][CH2:57][CH:52]([C:50]([C:42]4[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=5[N:43]=4)=[O:51])[CH2:53][CH2:54]3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)=[O:8])=[C:5]([O:30][C:31](=[O:33])[CH3:32])[C:4]=1[O:34][CH3:35])[CH3:2]
Reactant: CCc1c(OC)cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)c(OC(C)=O)c1OC
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(CC)c(OC)c4OC(C)=O)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(4-ethyl acetoxy-3,5-dimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[C:22]([CH:27]3[O:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F-].[K+].[CH:37]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:43]3[CH:44]=[CH:45][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=3)=[C:22]([CH:27]3[O:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(C3OCCCO3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C3OCCCO3)c2)cc1
Yield: 94.6 %

Procedure:
3-{4-[1-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (560 mg, 1.05 mmol), potassium Fluoride (183 mg, 3.15 mmol), 4-isopropylphenyl boronic acid (344 mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium (121 mg, 0.105 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give the titled compound (570 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH2:51][CH2:52][CH2:53][C@H:46]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:50]2[CH2:49][CH2:48][N:47]3[CH2:51][CH2:52][CH2:53][C@@H:46]3[CH2:45]2)=[O:17])[CH:13]=1)(=[O:10])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.71 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide (6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (479 mg, 3.79 mmol). The reaction was stirred at room temperature for 3 hours, diluted with 2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate (2×25 mL). The combined aqueous layers were adjusted to pH 7 with buffer and re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was taken up in ethanol (25 mL) and concentrated to give the title compound.
Reaction SMILES: [C:1]1(=[O:10])[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH:2]12.Br[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[N:16][CH:17]=1>>[N+:18]([C:15]1[N:16]=[CH:17][C:12]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][CH2:8][CH2:9][CH:2]3[C:1]2=[O:10])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C1NCCN2CCCC12
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: O=C1C2CCCN2CCN1c1ccc([N+](=O)[O-])nc1
Yield: 42.8 %

Procedure:
Following general N—C coupling procedure 1, hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.202 g, 1.44 mmol), was combined with 5-bromo-2-nitropyridine (0.293 g, 1.44 mmol, 1.0 eq) which gave 2-(6-Nitro-pyridin-3-yl)hexahydro-pyrrolo[1,2-a]pyrazin-1-one as a tan solid (0.170 g, 0.616 mmol) in 43% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.79-2.19 (m, 1H) 2.31 (br. s., 1H) 2.77 (br. s., 1H) 2.98-3.16 (m, 1H) 3.26 (dt, J=12.05, 4.52 Hz, 1H) 3.47 (br. s., 1H) 3.80 (br. s., 1H) 3.95-4.23 (m, 1H) 8.15 (dd, J=8.53, 2.51 Hz, 1H) 8.32 (d, J=8.53 Hz, 1H) 8.70 (d, J=2.51 Hz, 1H). MS m/z 263.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:12](O)=[O:13])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[CH3:44][NH:45][NH2:46]>ClCCl>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:12]([N:45]([CH3:44])[NH2:46])=[O:13])=[CH:5][CH:4]=1
Reactant: CNN
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C(=O)N(C)N)cc2OCc2ccc(OC)cc2)cc1
Temperature: -40 °C
Yield: 97.4 %

Procedure:
3,4-bis-(4-Methoxybenzyloxy)benzoic acid (0.792 g, 2.0 mmol) was dissolved in dichloromethane (20 ml) and treated with N,N-diisopropylethylamine (0.35 ml, 2.0 mmol). The solution was cooled to -40° C. and treated with methanesulphonyl chloride (0.15 ml, 2.0 mmol). The mixture was allowed to warm to room temperature for 10 minutes and then re-cooled to -40° C. and added to a solution of methylhydrazine (0.215 ml, 4 mmol) in dichloromethane (10 ml) at -40° C. The mixture was allowed to warm to room temperature for 1.5 h and then evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate which was washed with water and brine. Evaporation of the solvent gave the title compound (0.823 g, 94%); δH (CDCl3) 3.08 (3H, s), 3.74 (6H, s), 4.25 (2H, brs), 5.03 (4H, s), and 6.70- 7.40 (11H, m).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[N:4]=[CH:3]1.[C:12]12([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.N>>[C:12]12([CH2:22][C:23]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[S:9][CH:10]=[CH:11][C:5]=4[N:4]=[CH:3]3)=[O:24])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1cnc2ccsc2c1=O
Agent: N
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccsc2c1=O

Procedure:
3-Amino-3,4-dihydrothieno[3,2-d]pyrimidin-4-one and 1-adamantaneacetyl chloride were reacted as described in Example 1: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.68 (m, 12H), 1.94 (br s, 3H), 2.10 (s, 2H), 7.46 (d, J=5.4 Hz, 1H, 11.15 (s, 1H) ppm; MS (DCI/NH3) m/z 344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10]N(CC)CC)[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19].ClC1C=C(OC[CH2:31][CH2:32][N:33]([CH2:36]C)[CH2:34][CH3:35])C=CC=1C(=O)CCC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:36][N:33]([CH2:34][CH3:35])[CH2:32][CH3:31])[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19]
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: CCCC(=O)c1ccc(OCCCN(CC)CC)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCCCN(CC)CC)cc1Cl

Procedure:
This compound is prepared by essentially the same method as described in Example 1 Step B except that the 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone of Example 1 Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(3-diethylaminopropoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.4 mm.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:33])[C:13](=[O:32])[N:14]([C:15]4[C:16]([CH3:31])=[N:17][N:18]([CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[CH2:34]([NH:36][C:37]1[C:38]([CH3:52])=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)[CH3:35]>>[CH2:34]([NH:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:33])[C:13](=[O:32])[N:14]([C:15]5[C:16]([CH3:31])=[N:17][N:18]([CH2:21][CH2:22][OH:23])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:40]=[N:39][C:38]=1[CH3:52])[CH3:35]
Reactant: Cc1nn(CCO[Si](C)(C)C(C)(C)C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(CCO)c2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-Bromo-1-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 210.1.1) and ethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 87.1.1) to give the title compound as an off-white solid; deprotection of the silyl group occurred during the purification step. (HPLC: tR 2.16 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.10-8.06 (m, 1H), 7.94-7.90 (m, 1H), 7.85-7.82 (m, 1H), 7.55-7.52 (m, 1H), 6.83-6.80 (m, 1H), 5.21 (t, 1H), 4.92 (t, 1H), 4.21-4.03 (m, 2H), 3.81-3.67 (m, 2H), 3.59 (s, 3H), 3.24-3.14 (m, 2H), 2.32 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H), 1.24 (t, 3H))
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([F:20])[C@H:17]([OH:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([F:20])[C@H:17]([OH:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: O[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1F
Temperature: 75 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
A mixture of 50 mg of 2-benzyl-6-[(3R,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl]-3-iodopyridine, 21 mg of (3R)-3-ethynyl-3-quinuclidinol, 15 mg of tetrakis(triphenylphosphine)palladium(0), 1 mg of cuprous iodide, 53 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring for 3 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia, was then extracted with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 37 mg of the target compound.