Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@]1(O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)O.[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:25][C@@H:23]1[OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)C1C=CC=CC=1.[OH-].[K+]>O>[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[O:25][C@@H:23]1[O:24][CH3:1])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@]1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCc1ccccc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
Preparation of 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranose Methyl-α-D-glucopyranose (100 g, 0.516 mol) is suspended in benzyl chloride (400 mL, 3.5 mol) with KOH pellets (336 g, 6 mol), and the mixture is stirred using a mechanical stirrer at 120°-130° C. for 3 h. The reaction mixture is cooled and water (800 mL) is added to dissolve the crystalline mass, which is extracted with ether (2×200 mL). The combined organic layer is washed with water (2×500 mL) and dried (Na2SO4). The solvents are removed by vacuum distillationto give the crude methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside for the next reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][NH:18]C(=O)O)=[C:10]3[S:22][C:23]4[CH:28]=[C:27]([O:29]C)[CH:26]=[CH:25][C:24]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].B(Br)(Br)Br.CO>ClC(Cl)C.ClCCl>[NH2:18][CH2:17][CH2:16][NH:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]([CH2:5][CH2:4][N:3]([CH2:31][CH3:32])[CH2:1][CH3:2])[N:7]=[C:8]3[C:24]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=4[S:22][C:10]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c(NCCNC(=O)O)ccc31)Sc1cc(OC)ccc1-2
Agent: BrB(Br)Br
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)Sc1cc(O)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 154 %

Procedure:
A 25° C. solution of 0.25 g (0.49 mmol) of [2-[[2-[2-(diethylamino)ethyl]-8-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazol-5-yl]amino]ethyl]-carbamic acid; 1,1-dimethylethyl ester (6) in 7.5 mL of dichloroethane was treated dropwise with 2.45 mL (2.45 mmol) of a 1M solution of boron tribromide in dichloromethane. The mixture was stirred at 25° C. for 18 hr, treated cautiously with 3 mL of methanol, then heated at reflux for 6 hr. After cooling to 25° C., the precipitated solids were collected by filtration, washed successively with methanol and dichloromethane, and dried at 200 mm/60° C./overnight to give 0.3 g of 4, 95.2% pure by HPLC. The solids were dissolved in 10.6 mL of ethanol:H2O (4:1) and the solution was treated portionwise with 1.6 mL of a 2.6M solution of hydrogen bromide in 2-propanol. After standing overnight at 0°-5° C., the precipitated solids were collected by filtration, washed, and dried as above to give 0.28 g (90%) of 4 as a salt with 2.9 equivalents of hydrogen bromide, mp 282° C. (dec), 96.1% pure by HPLC.
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH:16]=[C:17]([CH3:19])[O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7].[C:21](O)([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:6]([C:10]1[C:15]2[CH:16]=[C:17]([CH3:19])[O:18][C:14]=2[CH:13]=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]=1[OH:20])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)O
Reactant: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(C(C)(C)C)c(O)c(C(C)(C)C)cc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11.2 %

Procedure:
Methanesulfonic acid (1.2 ml) was added dropwise to a chloroform solution of 4-tert-butyl-5-hydroxy-2-methylbenzofuran (250 mg, 1.2 mmol) and tert-butyl alcohol (500 mg, 6.0 mmol) under cooling with ice. After stirring at 0° C. for 15 min, the mixture was poured into ice water. The mixture was then neutralized with 1N aqueous sodium hydroxide and subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2-methylbenzofuran (35 mg) as a pale yellow oil. Mass 260(M+), 245, 57
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:8][C:9]#[N:10].[K+]>C(O)(=O)C.O>[C:2]1([NH:1][C:9]([NH2:10])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of aniline (2.51 g, 27 mmol) dissolved in glacial acetic acid (14 mL) and water (28 mL) was slowly added a solution of potassium cyanate (4.4 g, 54 mmol) dissolved in water (35 mL). The mixture stirred for 2 h at RT, filtered, washed with water and dried under reduced pressure to yield phenylurea as a white solid (1.85 g, 50% yield). 1H NMR (DMSO-d6): δ 8.47 (s, 1H), 7.38 (dd, J=8.4 Hz, 0.9 Hz, 2H), 7.2 (t, J=7.6 Hz, 2H), 6.88 (t, J=7.6 Hz, 1H), 5.81 (brs, 2H); MS (ESI) m/z: 137 (M+H+).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[C@H:21]([NH:22][C:23](=[O:34])[C:24](=[N:31][O:32][CH3:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:35])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[C:41]([O-])(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CS(C)=O>[C:1]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[C@H:21]([NH:22][C:23](=[O:34])[C:24](=[N:31][O:32][CH3:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:35])[N:15]2[C:16]=1[C:17]([O:19][CH:41]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)c3ccccc3)CS[C@H]12)c1ccccc1

Procedure:
3-Benzoyloxymethyl-7β-(2-methoxyimino-2-phenylacetamido)-ceph-3-em-4-carboxylic Acid (syn-isomer) as a white powder (48%) [α]D + 46.5° (c 0.9 in DMSO) λmax. (pH 6 phosphate buffer) 232.5 (ε 22,400) and 258.5 nm (ε 21.400) λmax. (Nujol) 1780 (β-lactam), 1720 and 1265 (benzoate), 1705 (CO2H), 1675 and 1532 cm-1 (CONH) τ (DMSO-d6, 100 MHz) 0.16 (doublet, J 8 Hz; NH) 4.06 (double doublet J 5 and 8 Hz; C-7H), 4.70 (doublet; J5 Hz; C-6 H), 6.03 (singlet; NOCH3), and 6.14 and 6.44 [2 doublets (branches of quartet), J 18 Hz; C-2 CH2 ].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16](=[O:17])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)CC(Cc1ccccc1)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C1CC(c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)Cc2ccccc21

Procedure:
3-(4(p-trifluoromethylphenoxy)phenyl)-4-phenylbutyric acid (23 g) was refluxed in benzene with thionyl chloride (46 ml) for one hour. The solution was then evaporated to dryness and the residue dissolved in benzene (23 ml). A solution of stannic chloride (23 g) in benzene (46 ml) was added at 0° with stirring. The solution was allowed to stir at 0° for 0.5 hr. Ice; water, diethylether and dilute HCl were then added sequentially. The ether extracts were further washed with aqueous potassium hydroxide and evaporated to give 3-(4-(p-trifluoromethylphenoxy)phenyl)tetralone m.p. 136°-137° (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 4 h
Yield: 37 %

Procedure:
DMAP (89 mg, 0.73 mmol), p-anisidine (0.10 g, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional p-anisidine (45 mg, 0.37 mmol) was added. The reaction was diluted with EtOAc after another 17 h and washed with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated impure product. It was then crystallized from EtOAc/heptane, triturated with pentane, and recrystallized from EtOAc/heptane to give 0.14 g (36%) of a white solid: mp 143.0-144.0° C.; 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 7.47 (m, 3H), 7.25 (d, J=8.7 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 5.04 (br s, 2H), 3.71 (s, 3H), 3.63 (m, 4H), 3.39 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 2975, 1666, 1545, 1514, 1474, 1451, 1414, 1365, 1253, 1239, 1222, 1173, 1158, 830, 784 cm−1; MS (EI) m/z 517 (M+), 377, 375, 227, 224, 212, 134, 124, 121, 55, 53; MS (FAB) m/z 518 (M+H+), 520, 519, 518, 517, 464, 463, 462, 461, 418, 57; HRMS (EI) calcd for C26H29Cl2N3O4 517.1535, found 517.1537; Anal. Calcd for C26H29Cl2N3O4: C, 60.24; H, 5.64; N, 8.10; found: C, 59.86; H, 5.68; N, 7.94.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(OC)cc3)CC2)n(-c2ccccc2)n1

Procedure:
122 mg (65%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(4-methoxyphenyl)piperazine (80 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:24])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC(C)C)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (56 mg, 0.154 mmol) and TBTU (55 mg, 0.169 mmol) in DMF (2.0 mL) was added DIPEA (131 μL, 0.769 mmol). Then isopropylamine (15 μL, 0.169 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (47 mg, 75%) as a white solid. MS: m/e=406.4 [M+H]+.
Reaction SMILES: [S:1]([O:11][CH2:12][CH2:13][CH2:14]O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O-:11])(=[O:3])=[O:2].[OH:11][CH2:12][CH2:13][CH2:14][N+:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCO)cc1
Reactant: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: OCCC[n+]1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In 10 ml of pyridine was dissolved 4.0 g of 1,3-propanediol monotosylate and the mixture was stirred at 60° C. overnight. The mixture was concentrated under reduced pressure to give the desired compound as a colorless oily material. Yield: 5.6 g (quantitative).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[CH:25]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([CH:7]=1)[C:1]([O:11][CH3:12])=[O:10])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccccc1OC
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1cc(C=O)ccc1OC

Procedure:
16.6 g of methyl o-anisate was dissolved in 100 ml of trifluoroacetic acid. Thereto was added 14.0 g of hexamethylenetetramine with ice-cooling. The mixture was refluxed for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was poured into 120 ml of water. The mixture was neutralized with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=2/1) to obtain 16.1 g of methyl 5-formyl-2-methoxybenzoate. It was recrystallized from diisopropyl ether to obtain 14.0 g of colorless crystals having a melting point of 85°-86° C.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:29][O:28][CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[CH:12]=[N:11][C:6]4[NH:7][C:8]5[CH:9]=[N:10][C:2]([C:34]6[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=6)=[CH:3][C:4]=5[C:5]=4[CH:14]=3)=[CH:16][CH:17]=2)[CH2:23][CH2:24]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(-c6cnn(C)c6)cc5c4c3)cc2)CC1
Temperature: 130 °C
Yield: 41.7 %

Procedure:
A degassed mixture of 6-bromo-3-[4-(4-methoxypiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.16 g, 0.36 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.72 mmol) and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II) (29 mg, 0.036 mmol) in acetonitrile (3.6 mL) and saturated aqueous sodium carbonate solution (3.6 mL). The reaction mixture was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was partitioned between DCM and water. The organic phase was dried over sodium sulfate, filtered and evaporated and the resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as a yellow solid (68 mg, 42%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (d, J=2.2 Hz, 1H), 8.30 (d, J=1.1 Hz, 1H), 8.06-8.04 (m, 2H), 7.71 (d, J=7.9 Hz, 2H), 7.52 (d, J=2.0 Hz, 2H), 4.01 (s, 3H), 3.74-3.63 (m, 2H), 2.94-2.79 (m, 2H), 2.47-2.25 (m, 2H), 2.04-1.90 (m, 2H), 1.78-1.58 (m, 2H). LCMS (Method A): RT=4.76 min, M+H+=453.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:27][I:28]>CC(C)=O>[I-:28].[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]([NH:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3][N+:2]2([CH3:27])[CH3:1])=[O:18])=[CH:24][CH:23]=1
Reactant: CI
Reactant: COc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2CCC2CCCC[N+]2(C)C)cc1
Product: [I-]

Procedure:
A solution of 7.04 g (0.020 mol) of encainide (I) and 5.68 g. (0.040 mol) of methyl iodide in 100 ml. of acetone was heated at the reflux temperature for 24 hours. The solvent was evaporated and the residue was distributed between H2O and benzene. The aqueous layer was separated, washed twice with benzene, and evaporated in vacuo to obtain a solid, m.p. 75°-80° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]([F:53])([F:52])[C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[C:48]3[CH:49]=[CH:50][S:51][C:47]=3[CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:53][C:36]([F:35])([F:52])[C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[C:48]3[CH:49]=[CH:50][S:51][C:47]=3[CH2:46][CH2:45][N:44]2[C:7]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=2)=[O:9])=[CH:41][CH:42]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3sccc32)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)c1ccc(C(=O)N2CCc3sccc3C2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Dimethylaminobenzoic acid (0.20 g, 1.2 mmol) was dissolved in N,N-dimethylformamide (3 ml) and 1-hydroxybenzotriazole (0.20 g, 1.5 mmol) was added. To the resulting mixture N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.28 g, 1.5 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.41 g, 1.5 mmol) followed by diisopropylethylamine (0.42 ml, 2.4 mmol) were added and the mixture was stirred at room temperature for 16 hours. water (2 ml) was added and the mixture was extracted with ethyl acetate (2×5 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (4 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12.Br[C:11]1[N:28]([CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]2)[C:14]2[C:15]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)=[N:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=2[N:12]=1.[F-].[K+].CCN(C(C)C)C(C)C>CCOC(C)=O.CS(C)=O>[Cl:27][C:25]1[CH:26]=[C:21]([C:15]2[C:14]3[N:28]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:11]([N:1]4[CH2:6][CH2:5][NH:4][C@@H:3]5[CH2:7][CH2:8][CH2:9][C@@H:2]45)=[N:12][C:13]=3[CH:18]=[C:17]([C:19]#[N:20])[N:16]=2)[CH:22]=[N:23][CH:24]=1
Reactant: C1C[C@H]2NCCN[C@@H]2C1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](Cn2c(N3CCN[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added (4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazine (Preparative Example 5.2, 295 mg, 2.338 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 800 mg, 1.799 mmol), potassium fluoride (209 mg, 3.60 mmol), DMSO (8 ml), and DIEA (0.942 ml, 5.40 mmol). The reaction vial was capped and heated to 100° C. overnight. The mixture was then cooled to room temperature and diluted with EtOAc. The solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give crude 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H32ClN7 [M+H]+ 490. found 490.