Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH:20]2[C:15]([C:31]([OH:33])=O)([CH2:16][C:17]3[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=3[CH:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14][NH:13]1)=[O:11].[NH3:34]>ClCCl.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH:20]2[C:15]([C:31]([NH2:34])=[O:33])([CH2:16][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:19]2[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:17]=2)[CH2:14][NH:13]1)=[O:11]
Reactant: COc1ccccc1CC(=O)C1NCC2(C(=O)O)Cc3ccccc3C(c3ccccc3)C12
Reactant: N
Solvent: ClCCl
Solvent: CCO
Product: COc1ccccc1CC(=O)C1NCC2(C(N)=O)Cc3ccccc3C(c3ccccc3)C12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
467 mg (1 mmol) of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid and 200 mg (1.2 mmol) of N,N'-carbonyldiimidazole are dissolved in 20 cm3 of dry dichloromethane. 10 cm3 of a 0.5N solution of ammonia in ethanol are then added and the mixture is then stirred for 16 hours at a temperature in the region of 20° C. After diluting with 50 cm3 of dichloromethane, the reaction mixture is washed successively, by separation by settling, with 50 cm3 of a 4N hydrochloric acid solution and then with 2 times 25 cm3 of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained is recrystallized from 13 cm3 of ethyl acetate. 350 mg (75%) of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano-2-(2-methoxyphenyl)acetyl-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxamide are thus obtained in the form of white crystals, the characteristics of which are as follows: melting point=262-4° C., 1H N.M.R. spectrum (250 MHz, d6-(CD3)2SO, at a temperature of 383 K, δ in ppm): 1.36, 1.60, 1.88 and 2.05 (4 mts, each 1H, CH2CH2), from 3.20 to 3.65 (mt, 7H, CH2 at 1, COCH2Ar, 1H of the CH2 at 3, H at 4 and H at 9a), 3.67 (unresolved peak, 3H, OCH3), 4.22 (d, J=12.5 Hz, 1H, the other H of the CH2 at 3), 6.37 (broad d, J=7.5 Hz, 1H, H at 8), 6.75 (unresolved peak, 2H, CONH2), 6.88 (broad t, J=7.5 Hz, 1H, aromatic H para to the OCH3), 6.94 (broad d, J=7.5 Hz, 1H, aromatic H ortho to the OCH3), 7.02 (dt, J=7.5 and 2 Hz, 1H, H at 7), from 7.05 to 7.30 (mt, 4H, H at 5, H at 6 and aromatic H meta to the OCH3), 7.39 (mt, 3H, aromatic H in the ortho and para positions of the phenyl at 9), 7.48 (t, J=7.5 Hz, 2H, aromatic H in the meta positions of the phenyl at 9).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1)=[O:5].[CH3:12][C@@H:13]1C[C@H:14]1C(=O)CC=C>>[O:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:4](=[O:5])[CH2:14][CH:13]=[CH2:12]
Reactant: CON(C)C(=O)[C@@H]1CCCO1
Reactant: C=CCC(=O)[C@@H]1C[C@H]1C
Product: C=CCC(=O)[C@@H]1CCCO1

Procedure:
(2S)—N-Methoxy-N-methyltetrahydrofuran-2-carboxamide (C92) was converted to the product using the method described for the synthesis of 1-[(1R,2R)-2-methylcyclopropyl]but-3-en-1-one (C80) in Example 20. The resulting product was used in the next step without further purification. Yield: 19 g, ≦0.14 mol, ≦87%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[N+:16]([O-])=O)=[CH:4][CH:3]=1.Cl[Sn]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[NH2:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Sc2ccc(F)cc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Sc2ccc(F)cc2)c(N)c1

Procedure:
The product from Example 49a was reduced with SnCl2 following the procedure from Example 1f giving the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([CH2:26]Br)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH2:22]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
Diethyl malonate (1.93 mL, 12.7 mmol) was added dropwise to a solution of NaH (60%; 0.51 g, 12.8 mmol) in dry THF (15 mL) at 0° C. The mixture was stirred at room temperature for 1 h after which it was added to a refluxed mixture of 3-bromomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.8 g, 10.6 mmol) in dry THF (30 mL). The reaction mixture was further refluxed for 19 h, and then concentrated to almost dryness. Water (1 L) was added, and the product was extracted with CH2Cl2. The combined organic phases were dried and concentrated under reduced pressure to yield 3.3 g of the crude product. Purification by flash chromatography (CH2Cl2/EtOAc: 1/0→68/32) afforded 2-(1-tert-butoxycarbonyl-pyrrolidin-3-ylmethyl)-malonic acid diethyl ester (1.64 g, 45%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)=O.[OH:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOCCOCCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
34.04 g (0.105 moles) of 2-(2-butoxyethoxy)-ethyl tosylate (95%) were reacted with 14.5 g (0.105 moles) of 5-hydroxy-benzo[1.3]dioxole and 14.5 g (0.105 moles) of anhydrous potassium carbonate in 125 ml of acetone. The mixture was heated to reflux for 2 hrs, cooled to room temperature and kept, under stirring, at that temperature for 6 hrs. The mixture was then filtered and the organic solution was evaporated u.v. (20° C./21 mbar) . The residue was diluted with 100 ml of dichloromethane and washed with 12 ml of an aqueous solution of sodium hydroxide 1N and water. The organic phase was separated, washed with water and evaporated u.v (20° C./21 mbar). An oil residue was obtained that was purified on silica gel column (eluant n-hexane:ethyl acetate 4:1 v/v). After evaporation 14.84 g (97.43%) of 5-[2-(2-Butoxy-ethoxy)-ethoxy]-benzo[1,3]dioxole were obtained whose NMR and MS analyses corresponded to those of the aforementioned compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](=[O:16])[CH3:15])[CH2:10]1.[Br:17]Br>ClCCl>[Br:17][CH2:15][C:14]([C:11]1[CH2:10][CH:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)C1=NOC(c2c(F)cccc2F)C1
Solvent: ClCCl
Product: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Temperature: 33 °C
Reaction time: 0.17 h

Procedure:
To a 500-mL flask equipped with a mechanical stirrer, thermometer, addition funnel and scrubber were added 1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e. the product of Step B) (60.0 g, 0.27 mmol) and dichloromethane (130 mL). The reaction mixture was heated at 33° C., and a solution of bromine (39.2 mL, 0.24 mol) in dichloromethane (100 mL) was added dropwise via the addition funnel. After about 5 mL of the bromine solution had been added, the addition was stopped and the reaction mixture was stirred at 33° C. for about 10 minutes, during which time the color of the reaction mixture changed from red to yellow. The reaction mixture was cooled to 5° C., and the remaining bromine solution was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was washed with sodium bisulfite solution (3.5 g in 100 mL of water). The organic layer was concentrated under reduced pressure, hexanes were added, and the resulting solid precipitate was collected by filtration and washed with hexanes to provide the title compound as a brown solid (73 g), which was used without further purification
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16]CC)=O)[CH2:7][CH2:6]2)OC=C1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=C[C:39]([O:42]C2C=CC=CC=2)=[CH:38]C=1>>[CH2:38]1[O:20][C:19]([C:13]2[CH:12]=[N:11][C:8]3[CH2:9][CH2:10][C:5](=[O:1])[CH2:6][C:7]=3[C:14]=2[OH:16])([O:21][CH2:22][CH3:23])[O:42][CH2:39]1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(=CNC1CCC2(CC1)OC=CO2)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC1(c2cnc3c(c2O)CC(=O)CC3)OCCO1
Temperature: 25 °C

Procedure:
Diethyl N-(1,4-dioxaspiro[4.5]decen-8-yl)aminomethylenemalonate (53 g) in 100 ml of Dowtherm is added to 400 ml of Dowtherm at reflux and the mixture is heated at 250° for 45 minutes. The low boiling distillate is collected in a Dean-Stark trap. After cooling to room temperature, the mixture is evaporated to dryness in vacuo, and the residue is triturated with Et2O to give ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate ethylene ketal.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.Cl.[CH2:13]([NH:16][OH:17])[CH2:14][CH3:15]>CO>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([N:16]([CH2:13][CH2:14][CH3:15])[OH:17])[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2c1CCC=C2
Reactant: CCCNO
Agent: Cl
Solvent: CO
Product: CCCN(O)C1CCc2c(Cl)ccnc2C1
Yield: 85.5 %

Procedure:
This compound was prepared from the product of Step 4 (4.35 g, 26 mmol), 1-propylhydroxylamine hydrochloride (6 g, 54 mmol), and methanol (10 ml) by the method described in Example 10. The residue was recrystallised from cyclohexane to give the product (5.35 g).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH2:31][CH3:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CC#N
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O

Procedure:
Methanesulfonic anhydride (0.6 g, 3.4 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol) and acetonitrile (200 ml). A precipitate formed within a few minutes. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The fractions were separated and the organic fraction was dried (MgSO4), filtered and concentrated to yield the crude product as a white solid. Recrystallization from methyl acetate provided N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a white crystalline solid, m.p. 195.1-196.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=7.4 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H), 7.50 (dt, J=7.5, 1.1 Hz, 1H), 7.26 (dt, J=7.5, 1.2 Hz, 1H), 6.99 (t, J=5.7 Hz, 1H), 6.44 (broad s, 2H), 4.52 (t, J=7.5 Hz, 2H), 3.02-2.86 (m, 7H), 1.82 (m, 4H), 1.62 (m, 2H), 1.46 (q, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3348, 3299, 3152, 2952, 2931, 2869, 1642, 1584, 1530, 1480, 1323, 1155, 1142, 1094, 982, 765 cm−1; MS (EI) m/e 389.1889 (389.1885 calcd for C19H27N5O2S); Anal calcd for C19H27N5O2S: C, 58.59; H, 6.99; N, 17.98. Found: C, 58.26; H, 6.64; N, 17.69
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([O-:14])=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1.[Li+].[OH-].Cl>C1COCC1.CO>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: O=C([O-])c1cnc2cc(C(F)(F)F)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2cc(C(F)(F)F)ccn12
Temperature: 60 °C

Procedure:
To a stirring solution of ethyl 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (23) (100 mg, 0.387 mmol) in THF:MeOH (4:1, 1.5 mL) was added 2N LiOH (0.25 mL). The reaction was heated at 60° C. for 1 hour. Then, cooled to room temperature and the pH was adjusted between 4-5 with 1N HCl. The solvent was partially concentrated and the resulting aqueous layer was lyophilized to give 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24). 1H NMR (400 MHz, d6-DMSO) δ 9.44 (d, J=7.2 Hz, 1H), 8.40 (s, 1H), 8.31-8.30 (m, 1H), 7.48 (dd, J=2.0, 7.6 Hz, 1H). MS m/z 231.2 (M+1)+.
Reaction SMILES: N1C2C(=CC=CC=2)C[CH2:2]1.[CH2:10]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:31]([OH:33])=[O:32])=[C:24]([CH3:30])[C:25]=2[N+:27]([O-:29])=[O:28])[CH2:20][CH2:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].S(=O)(=O)(O)O>CO>[CH2:10]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:31]([O:33][CH3:2])=[O:32])=[C:24]([CH3:30])[C:25]=2[N+:27]([O-:29])=[O:28])[CH2:20][CH2:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCCCCCCCN1CCc2cc(C(=O)O)c(C)c([N+](=O)[O-])c21
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCCCCCN1CCc2cc(C(=O)OC)c(C)c([N+](=O)[O-])c21

Procedure:
0.88 (3H, br-t, J=7 Hz, —(CH2)7CH3), 1.00˜1.70 (121H, m, —H2(CH2)f—), 2.47 (3H, s, indoline C6—CH3), 3.02 (2H, t, J=8 Hz, indoline C3—H2), 3.03 (2H, t, J=7 Hz, >NCH2—), 3.69 (2H, t, J=8 Hz, indoline C2—H2), 5.00 (IH, br, -2H), 7.73 (1H, s, indoline C4—H). (4) 1-Octyl-5-carboxy-6-methyl-7-nitroindoline (1.4 g) was dissolved in methanol (30 ml), and conc. sulfuric acid (4.1 g) was added, which was followed by refluxing for 4 hr. Methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/ methanol=1/10−10/1) to give 750 mg of 1-octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCCC(COCc2ccc(-c3ccc(Cl)cc3)cc2)C1
Yield: 85.5 %

Procedure:
Using 1-(tert-butoxycarbonyl)-piperidin-3-yl methanol (431 mg, 2.00 mmol) and 4′-chloro-4-chloromethylbiphenyl (474 mg, 2.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 711 mg (86%) of the desired compound as a colorless oil.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15](=[O:32])[NH:16][C:17]2[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([O:25]C(C)C)=[O:24])=[CH:19][C:18]=2[CH3:31])=[O:13])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].O.Cl>C(O)(=O)C>[C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15](=[O:32])[NH:16][C:17]2[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][C:18]=2[CH3:31])=[O:13])=[CH:33][CH:34]=1)(=[NH:6])[NH2:7]
Reactant: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C(=N)N)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCC(=O)O)ccc1NC(=O)NC(=O)c1ccc(C(=N)N)cc1
Reaction time: 72 h
Yield: 63.8 %

Procedure:
A mixture of isopropyl 4-[3-(4-amidinobenzoyl)ureido]-3-methylphenoxyacetate, acetate salt (500 mg), water (50 ml), 50% aqueous acetic acid (1.5 ml) and 2N HCl (1.5 ml) was stirred and heated to 90°-100° C. until all the solids had dissolved. The hot solution was then quickly filtered and the filtrate was heated to 80°-85° C. and stored at that temperature for 3 days. The mixture was cooled and the solid was collected, washed thoroughly with water, methanol and with ether. The solid was suspended in refluxing methanol/dichloromethane, 4:1 (50 ml). The insoluble material was collected, washed with hot methanol and with ether and dried to give the title compound (250 mg), as a pale yellow solid: NMR Spectrum (DMSO-d6 +CF3CO2H) 2.30 (3H, s), 4.66 (2H, s), 6.81 (1H, dd), 6.89 (1H, d), 7.78 (1H, d), 7.97 (2H, d), 8.24 (2H, d), 9.17 (2H, br s), 9.48 (2H, br s), 10.51 (1H, s), 11.25 (1H, s); m/Z 371 (M+H)+ ; Elemental Analysis: calculated for C18H18N4O5. 1.25 H2O: C, 55.0%; H, 5.26%; N, 14.3%; found: C, 54.9%; H, 5.3%; N, 14.2%.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]=[CH:9][C:8]=1[Cl:21])(=O)(=O)C.[C-:22]#[N:23].[Na+].O>CS(C)=O>[Cl:21][C:8]1[CH:9]=[CH:10][C:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][C:7]=1[CH2:6][C:22]#[N:23]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a stirred solution of 2-chloro-5-(Boc-amino)benzyl mesylate (from step (ii) above) in DMSO was added NaCN (2.9 g; 60 mmol), and the solution was stirred at room temperature overnight. The mixture was poured into water (300 mL) and the water suspension was extracted with ether (4×50 mL). The combined organic layers were washed with water, dried (Na2SO4), and concentrated. After flash chromatography (Si-gel; heptane:EtOAc (8:2)), 5.2 g (65%) of the sub-title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COCCN1CCNCC1
Solvent: CN(C)C=O
Product: COCCN1CCN(Cc2ccc(Br)cc2)CC1
Yield: 64.2 %

Procedure:
4-Bromobenzyl bromide (2.0 g) and 1-(2-methoxyethyl)piperazine (2.31 g) were stirred in dimethylformamide (30 ml) for 18 h. The mixture was partitioned between diethyl ether (30 ml) and water (30 ml). The aqueous phase was extracted further with ether (30 ml) and the combined organics were washed with water (50 ml), dried (MgSO4), concentrated in vacuo and purified by Bondelute® chromatography, eluting with 0-100% ethyl acetate/iso-hexane followed by 10-50% methanol/ethyl acetate to give the product as a yellow oil (1.61 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[C:9]([C:13]#[N:14])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.BrC1C2N(CC(O)=[O:27])C=NC=2C=CC=1>>[C:13]([C:9]1[C:8]2[N:4]([CH2:3][C:2]([OH:27])=[O:1])[CH:5]=[N:6][C:7]=2[CH:12]=[CH:11][CH:10]=1)#[N:14]
Reactant: N#Cc1cccc2ncn(CCO)c12
Reactant: O=C(O)Cn1cnc2cccc(Br)c21
Product: N#Cc1cccc2ncn(CC(=O)O)c12

Procedure:
(7-Cyano-1H-benzimidazol-1-yl)acetic acid was prepared starting from 1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile (89 mg) according to the procedure described for the synthesis of (7-bromo-1H-benzoimidazol-1-yl)acetic acid. Yield 38 mg (39 %). MS (ESI) m/z 202.0 [M+H). 1H NMR (400 MHz, DMSO-D6) δ ppm: 5.31 (s, 2 H), 7.37 (dd, J=8.1, 7.7 Hz, 1H), 7.75 (dd, J=7.6, 0.8 Hz, 1H), 8.04 (dd, J=8.1, 1.1 Hz, 1H), 8.38 (s, 1H), 13.43 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: Oc1ccccc1F
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccccc1F
Yield: 17 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-fluorophenol (17 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 11 mg (17%) of the titled compound. ESI-MS m/z 386 (MH+), 384 (M−H−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:18]([I:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[I:24][C:18]1[C:17]([O:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=[C:20]([CH3:23])[N:19]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (229 mg), 3-hydroxy-2-iodo-6-methylpyridine (486 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. overnight. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-chloroform to give the title compound (47 mg, yield 11%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH2:24][CH3:25])=[C:17](/[F:23])\[C:18](OCC)=[O:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH2:24][CH3:25])=[C:17](/[F:23])\[CH2:18][OH:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C=CCC2(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-enoate (Compound A-41, 52 mg, 0.15 mmol) and diisobutylaluminum hydride (1M in methylene chloride, 0.36 mL, 0.36 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH2:13][CH3:14])[N:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH:13]([Br:15])[CH3:14])[N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1CC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)nc1C(C)Br

Procedure:
A solution of ethyl 6-chloro-2-ethylnicotinate (1.0 g, 4.7 mmol), N-bromosuccinimide (0.85 g, 4.8 mmol) and benzoyl peroxide (10 mg) in 10 ml of carbon tetrachloride is heated to reflux while irradiated with a floodlamp for 3 hours. The reaction mixture is cooled and the solid succinimide is removed by filtration. The solid is washed several times with carbon tetrachloride and the filtrate is stripped by rotoevaporation to give ethyl 6-chloro-2-(1-bromoethyl)nicotinate.