Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N:33](S(C)(=O)=O)[S:34]([CH3:37])(=[O:36])=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)N(c1cnccc1OCc1ccccc1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Tetrabutylammonium fluoride 1 M in THF (12.2 ml, 42 mmol, 2.5 eq) was added to a solution of N-(4-(benzyloxy)pyridin-3-yl)-N-(methylsulfonyl)methane sulfonamide (6 g, 16.8 mmol, 1 eq) in THF at room temperature. The reaction mixture was refluxed at 60° C. for 10 h. The solution was concentrated completely and diluted with water (5 mL) and was allowed to stir for 15 minutes, The solid precipitated was filtered, washed with water and dried under vacuum yielding the expected product as a pale brown solid. 1HNMR (400 MHz, DMSO-d6): δ 335 (s, 3H), 5.27 (s, 2H), 7.21 (d, J=5.64 Hz, 1H), 7.36-7.54 (m, 3H), 7.54 d, J=7.28 Hz, 2H), 8.30 (s, 1H), 8.33 (d, J=5.64 Hz, 1H), 9.34 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]([CH3:27])([C:20]([O:22]C(C)(C)C)=[O:21])[CH3:19])=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:28])[CH:5]=[CH:4][C:3]=1[C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37].C(O)(C(F)(F)F)=O.CCOCC>C(Cl)Cl>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]([CH3:19])([C:20]([OH:22])=[O:21])[CH3:27])=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:28])[CH:5]=[CH:4][C:3]=1[C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)Cc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)(NC(=O)Cc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To a solution of Intermediate 16 (0.05 g, 0.095 mmol) in DCM (2 ml) was added TFA (1 ml). The reaction mixture was stirred at RT for 5 hours and then concentrated under reduced pressure to leave a yellow oil. Trituration with Et2O afforded the title compound as an off-white solid (42 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3)O2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 73.2 %

Procedure:
To a solution of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.05 g, 5.21 mmol) and phenylboronic acid (0.952 g, 7.81 mmol) in dioxane (50 mL) heated to 100° C. was added dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.205 g, 0.261 mmol) and potassium carbonate (1.80 g, 13.04 mmol) and the reaction mixture was allowed to stir at 100° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (250 mL), and filtered (celite). The organic layer was washed with water (2×100 mL) and saturated aqueous sodium chloride (100 mL), was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 1.45 g (73%) of (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a clear oil. Rf=0.34 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C22H20O4S: C, 69.45; H, 5.30. Found: C, 69.17; H, 5.30.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=1.[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][NH2:31])=[CH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][NH:31][C:13](=[O:15])[C:10]3[CH:9]=[CH:8][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[CH:12][N:11]=3)=[CH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cn1
Reactant: Cc1cc(-c2ncc(CN)cc2C)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(-c2ncc(CNC(=O)c3ccc(-c4cnccn4)cn3)cc2C)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(pyrazin-2-yl)picolinic acid 41-4 (20 mg, 0.1 mmol), (2′,3-dimethyl-2,4′-bipyridin-5-yl)methanamine 63-2 (21 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (38 mg, 0.1 mmol) in DMF (1.0 mL) was added DIEA (0.053 mL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-((2′,3-dimethyl-2,4′-bipyridin-5-yl)methyl)-5-(pyrazin-2-yl)picolinamide 63 as white solid. MS m/z 397.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.59 (t, 1H), 9.39 (d, 1H), 9.33 (d, 1H), 8.76 (m, 1H), 8.68 (m, 2H), 8.45 (d, 1H), 8.15 (d, 1H), 7.65 (d, 1H), 7.34 (b, 1H), 7.27 (d, 1H), 4.51 (d, 2H), 2.46 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH2:20][CH2:21][CH2:22]C1CCCNC1)[CH:10]=2)=[O:5])[CH3:2].Cl.[CH3:30][CH:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:42])=[CH:36][CH:35]=1)[CH3:32]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[N:46]1[CH2:45][CH2:44][N:43]([C:41](=[O:42])[NH:40][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:31]([CH3:30])[CH3:32])=[CH:35][CH:36]=3)[CH2:48][CH2:47]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH2:20][CH2:21][CH2:22][N:8]1[CH2:9][CH2:14][CH2:15][CH2:6][CH2:7]1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)N2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2cc(OCCCC3CCCNC3)c(OC)cc2c1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(OCCCN3CCCCC3)c(OC)cc2c1N1CCN(C(=O)Nc2ccc(OC(C)C)cc2)CC1
Temperature: 40 °C

Procedure:
To the DMF solution (3 mL) of the 4-chloroquinoline (0.175 g, 0.487 mmol) from step A added K2CO3 (0.155 g, 1.10 mmol) followed by N-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.169 g, 0.535 mmol). The reaction mixture was heated to 40° C. overnight, during that period starting materials were consumed. After cooling diluted with EtOAc/water and the layers were separated. The organic layer was dried, filtered and evaporated to afford desired product as a crude residue. The crude residue was purified by RP-HPLC to afford 4-{4-(4-Isopropoxy-phenylcarbamoyl)piperazin-1-yl]-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-carboxylic acid ethyl ester (0.170 g, 50%). MS(ES) 634 (M+H)
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=4)[CH:16]=[C:11]3[C:10]([CH3:28])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:28][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3c(c2)c(C)nn3Cc2ccc(OC)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Temperature: 50 °C

Procedure:
To a stirred solution of N-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acrylamide (154) (70 mg) in CHCl3 (20 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture heated at 50° C. for 12. After completion of the reaction the solvents were removed, diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform twice. The organic layer was washed with brine solution and dried over sodium sulphate and the solvent completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound in 60% EtOAc/hexane gave pale yellow solid compound N-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acrylamide 155. 1H NMR (400 MHz, CDCl3) δ: 10.29 (s, H), 8.75 (d, J=2.07, 1H), 8.40 (d, J=1.95, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 7.43 (m, 1H), 6.50 (m, 1H), 6.46 (m, 1H), 6.26 (m, 1H), 2.55 (bs, 3H); MS m/z 277.9 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:10]=2)=O)[CH:2]=1.[Cl-].[OH:27][NH3+:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:28][OH:27])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:10]=2)[CH:2]=1
Reactant: [NH3+]O
Reactant: O=C(c1cccnc1)c1cccc(NS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: O=S(=O)(Nc1cccc(C(=NO)c2cccnc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.45 g (20 mmol) of the compound from Example 1, 2.08 g (30 mmol) of hydoxylammonium chloride and 4.14 g (30 mmol) of potassium carbonate are refluxed in 20 ml of ethanol for 15 h. After cooling to room temperature, the mixture is evaporated and the residue is stirred in 50 ml of water for 3 h (after this time no oily residues, but only crystalline residues, were still undissolved). The precipitate was filtered off, washed with water and recrystallised from methanol by addition of water. Yield: 5.71 g (73.7% of theory) M.p.: 170° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][C:25]([CH:22]5[CH2:24][CH2:23]5)=[O:26])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2)C1CC1
Yield: 37.2 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (200 mg, 0.72 mmol) and and cyclopropane carboxylic acid (80 mg, 0.93 mmol) according to the procedure described for example 93. Obtained the title compound as a white solid (93 mg, 37%),
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH2:20]=O.[ClH:22]>C(O)=O>[ClH:22].[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]1[CH3:20]
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(C(CO)CO)N(C)CC2
Reaction time: 10 h
Yield: 50 %

Procedure:
To 0.0125 mole (3.33 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 15 ml of a 37% aqueous formaldehyde solution and 15 ml of 99% formic acid are added. The reaction mixture is then kept at 100° C. for 10 hours. After cooling 50 ml of a 15% aqueous hydrochloric acid solution are added to the reaction mixture, which is then evaporated under reduced pressure. After thoroughly dehydrating the reaction mixture it is triturated with a small amount of acetone to yield the aimed compound with a melting point of 199° to 201° C. (ethanol/ether).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)([O-])O.[K+].CI.O>CN(C=O)C>[CH3:23][O:21][C:20](=[O:22])[CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C([O-])O
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
To a solution of N-benzyloxycarbonyl-DL-phenylalanine (155 g, 0.518 mol) in DMF (800 mL) were added mortar-pulverized potassium hydrogencarbonate (104 g, 1.04 mol) and methyl iodide (53 mL, 0.86 mol), and the mixture was stirred at room temperature for 5 hours. This reaction mixture was added to water (1800 mL) and extracted with ethyl acetate-hexane (4:1). The extract was washed successively with 2 portions of water (500 mL each), 5% sodium sulfite aqueous solution (500 ml) and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 164 g (100%) of N-benzyloxycarbonyl-DL-phenylalanine methyl ester as a colorless clear oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:19][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Solvent: CCO
Product: CC(C)NCCOc1cc(F)cc(S(C)(=O)=O)c1
Yield: 91 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and isopropylamine (1.15 ml, 13.46 mmol) in ethanol (4 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (421 mg, 90.9%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 173° C. MS m/z (relative intensity, 70 eV) 275 (M+, 4), 261 (16), 260 (41), 73 (32), 72 (bp).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1.N1C=CN=C1.C(Cl)Cl.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CC=C[C@H]1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC=C[C@H]1O

Procedure:
To a solution of rel-(1R,5R)-5-(hydroxymethyl)cyclopent-2-en-1-ol (47.20 g, 0.4135 mol), N,N-dimethylaminopyridine (2.52 g, 0.0207 mol) and 1H-imidazole (30.97 g, 0.4549 mol) in methylene chloride (800 mL, 10 mol) at 0° C. under an atmosphere of nitrogen was added tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol). The reaction was stirred for at 0° C. for 2.5 h, at which time tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol) was added. The reaction was stirred for 2 additional hours. The reaction was quenched by addition of saturated aqueous NaCl solution (200 mL) and water (200 mL). The layers were separated and the organic layer was washed with water (3×200 mL) and brine (1×200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The material was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[O:11].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[O:11])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cc(F)c(F)cc1C(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(F)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 117 mg of (2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.28 (s, 9H), 7.17 (t, 1H, J=8.4 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.54 (d, 2H, J=4.4 Hz), 7.64 (dd, 1H, J=11.6 Hz, 6.8 Hz), 7.72 (d, 2H, J=8.4 Hz), 8.85 (d, 2H, J=5.2 Hz), 10.42 (s, 1H). MS: m/z 431.1 (M++1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[CH:9][C:10]([O:12][CH3:13])=[O:11])[CH2:2]2>CCO.[Pd]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:2]2
Reactant: COC(=O)C=C1CN2CCC1CC2
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.2 %

Procedure:
A mixture of methyl 2-(quinuclidin-3-ylidene)acetate (70 mg, 0.38 mmol) and Pd/C (100 mg, 20% w/w) in EtOH (10 mL) was stirred under H2 (20 psi) at room temperature for 18 h. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure to afford crude methyl 2-(quinuclidin-3-yl)acetate (60 mg, 85%), which was used with purification in the next step.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]>CC(O)=O.CCOCC>[NH2:3][C:4]1[N:11]=[CH:10][C:9]([Br:1])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: BrBr
Reactant: N#Cc1cccnc1N
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.6 %

Procedure:
Bromine (1.1 mL, 21 mmol) in AcOH (3 mL) was added dropwise to a solution of 2-amino-nicotinonitrile (1.00 g, 8.4 mmol) in AcOH (20 mL) at 10° C. The orange mixture was stirred for 22 hours at ambient temperature then diluted with ether (100 mL). The resultant precipitated salt was filtered, washed with ether and dried on air. The precipitate was suspended in water (100 mL), neutralized with 1N NaOH, filtered, washed with water and dried on air to give 1.29 g (78%) title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=2.5 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 7.13 (s, br, 2H). MS (ESI) m/e: 197.9655 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:26]([O-:28])=[O:27].Cl.[CH3:30][O:31][CH2:32][CH:33]([NH2:35])[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:35][CH:33]([CH3:34])[CH2:32][O:31][CH3:30])[C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: COCC(C)N
Reactant: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Product: COCC(C)Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]
Yield: 104 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.50 g, 1.11 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine HCl (0.28 g, 2.22 mmol) were treated in the same manner as in Part C of Example 19a to produce 0.45 g (100%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 389.8 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25]C=CC=2)[CH:23]=[CH:22][CH:21]=1.CC1C=C(O)C=C([OH:37])C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:24]([CH3:25])[CH:23]=[C:22]([OH:37])[CH:21]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of ethyl 7-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (EXAMPLE 1C) (0.9 g), 5-methylbenzene-1,3-diol (1.028 g), triphenylphosphine (0.868 g), dibenzylazodicarboxylate (0.762 g) and tetrahydrofuran (40 ml) was stirred at room temperature for 19 hours. After removal of the solvent, the crude product was purified by flash chromatography silica gel, (Analogix, SF65-200 g) eluting with 0-10% ethyl acetate in hexane.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C@@H:21]2[O:39][C:24]3=[CH:25][N:26]=[C:27]([C:29]4[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:33][CH:34]=4)[CH:28]=[C:23]3[CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[CH3:38][S:35]([N:32]1[CH2:31][CH:30]=[C:29]([C:27]2[CH:28]=[C:23]3[CH2:22][C@H:21]([CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[O:39][C:24]3=[CH:25][N:26]=2)[CH2:34][CH2:33]1)(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (2 mL) is added to a solution of (R)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g) in dichloromethane (10 mL) at room temperature. The solution is stirred at room temperature overnight and then diluted with dichloromethane, 2 N aqueous NaOH solution, and saturated aqueous Na2CO3 solution. The resulting mixture is vigorously stirred for 20 min and then extracted with dichloromethane. The combined extract is dried (Na2SO4) and concentrated to give the title compound. Mass spectrum (ESI+): m/z=364 [M+H]+.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:15]C1C=C(C=CC=1)CBr.COP(OC)OC>>[CH3:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:2]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: Cc1cccc(CBr)c1
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Agent: COP(OC)OC
Product: COP(=O)(Cc1cccc(C)c1)OC

Procedure:
Following the procedure of Compound 11, 3-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=O)C.[N+:11]([CH2:14][C:15]([NH2:17])=[O:16])([O-:13])=[O:12].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH:8]1([C:6]2[NH:17][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1
Reactant: NC(=O)C[N+](=O)[O-]
Reactant: CN(C)C=CC(=O)C1CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Product: O=c1[nH]c(C2CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of crude b-N,N-dimethylaminoethenylcyclopropyl ketone (12 g, <86 mmol), nitroacetamide (9 g, 86 mmol) and aqueous piperidinium acetate (10 ml) [prepared from glacial acetic acid (42 ml), water (100 ml) and piperidine (72 ml)] was stirred at room temperature overnight. Following dilution with water (20 ml), the yellow precipitate was isolated via filtration and drying in vacuo to yield the title compound: 1H NMR (CDCl3) d 1.15 (m, 2 H), 1.36 (m, 2 H), 2.10 (m, 1 H), 6.02 (br d, J=8.0 Hz, 1 H), 8.41 (d, J=8.0 Hz, 1 H).