Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) and concentrated sulfuric acid (3.5 mL) in methanol (300 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate (250 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give 6-methyl-pyridine-2-carboxylic acid methyl ester (6.5 g, 59%) as a colorless oil. 1HNMR (CDCl3): δ 7.97 (d, J=7.6 Hz, 1H), 7.73 (dd, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 4.01 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:11]=1.ClCCl>O.Cl>[CH3:5][N:6]([N:1]=[O:3])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: CNCCCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(CCCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)N=O
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of sodium nitrite (7.2 g) in water (50 ml) was added slowly to a solution of N-methyl-3-[4-(trifluoromethyl)phenoxy]benzenepropanamine (30 g) and dichloromethane (100 ml) in 10% hydrochloric acid (200 ml). After one hr, the reaction mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica (eluted with 50% hexanes-dichloromethane). The appropriate fractions were collected and evaporated to give 28 g (95.4%) of product, mp 75°-76° C. Recrystallization from hexanes gave the analytical sample, mp 76°-77° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20]>CN(C)C=O>[F:20][CH:19]([F:21])[O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1F
Temperature: 85 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylformamide (15 mL) was added to 3-fluoro-4-nitrophenol (1.01 g, 6.43 mmol) and potassium carbonate (5.33 g, 38.6 mmol) in a 50 mL stainless steel reactor. The vessel was sparged briefly with CF2HCl, chilled with dry ice, and then chlorodifluoromethane (3.34 g, 38.6 mmol) was transferred into the reactor through a polypropylene tube. The mixture was stirred at 85° C. for 2 hours. The supernatant mixture was concentrated onto silica gel. Purification via flash chromatography (0-40% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.28 (t, J=9.16 Hz, 1 H), 7.51-7.57 (m, 1 H), 7.50 (t, J=72.39 Hz, 1 H), 7.21-7.29 (m, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[NH:19][N:20]=[C:21]([Cl:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[N:19]([CH3:28])[N:20]=[C:21]([Cl:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(Cl)n[nH]c(=O)c32)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(Cl)c2ccn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Temperature: 25 °C
Reaction time: 95 h
Yield: 86.4 %

Procedure:
In DMF (200 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-4-chloropyrrolo [2,3-d]pyridazin-7(6H)-one (830 mg) followed by addition of potassium carbonate (2.11 g). Then, methyl iodide (0.13 ml) was added and the mixture was stirred at room temperature for 95 hours. This reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water (100 ml) 3 times and further with saturated aqueous NaCl solution (100 ml) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting crystals were rinsed with ethyl acetate to provide 742 mg (yield 84%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[C:4]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)[N:7]=1)[CH2:9]2
Reactant: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1

Procedure:
4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)aniline was prepared by Suzuki coupling using the general method from scheme 2 for the preparation of 6 using 3-(2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (43, 1.63 g, 5.13 mmoles) and 4-aminophenyl boronic acid pinacol ester (1.24 g, 5.64 mmoles) as starting materials. The crude product was purified by chromatography on silica gel (eluting with 0-3% methanol in dichloromethane) to provide the desired compound as a light yellow solid. Yield: 1.80 g (94%). HRMS; [M+H]+ Obs'd=375.1485, [M+H]+ Calc'd=375.1485
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl.[NH2:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29])[CH3:18]>>[CH2:1]([O:8][C:9]([NH:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29])[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Benzyloxycarbonyl chloride (0.9 g) was dropwise added to an aqueous solution (10 ml) of (R)-4-(1-aminoethyl)-3-nitrobenzoic acid hydrochloride (1 g) and sodium hydroxide (535 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Conc. hydrochloric acid was added to the reaction mixture to make the same acidic. The mixture was extracted with chloroform. The extract was washed with water, dried, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 1.05 g of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoic acid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.C(O[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])C.[Cl-:28].[NH4+]>O1CCCC1>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]([C:3]2[CH:8]=[CH:7][C:6]([Cl:28])=[CH:5][CH:4]=2)([OH:14])[CH:15]2[CH2:16][CH2:17][N:18]([C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(C(=O)N(CC)CC)CC1
Reactant: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N1CCC(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A Grignard solution was prepared by the treatment of a slurry of 8.5 g (0.35 mole) of magnesium chips in 200 ml of dry tetrahydrofuran with a solution of 72.8 g (0.38 mole) of 1-bromo-4-chlorobenzene in 400 ml of tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 15 min to complete formation. To the Grignard solution at ambient temperature was added a solution of 38.4 g (0.15 mole) of 1-[(diethylaminocarbonyl]-4-piperidine carboxylic acid ethyl ester in 200 mo of tetrahydrofuran in a stream. The solution was stirred at ambient temperature overnight and poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted once with 500 ml of methylene chloride and once with 250 ml of methylene chloride. The combined organic layers were filtered through Celite® and the filtrate was washed successively with 500 ml of water, 750 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The solution was dried over sodium sulfate and concentrated under reduced pressure to give a gum which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 56.7 g (87%) of title compound as a white solid. An analytical sample was recrystallized from isopropanol, mp 172°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:10][CH:9]1[C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1)[S:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Sc1ccccc1
Reactant: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Solvent: CO
Product: COc1ccccc1OCCNCC(Sc1ccccc1)c1ccc(C)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
In 50 ml of methanol was dissolved 2.5 g of 5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide and after adding 1 g of thiophenol to the solution and stirring overnight the mixture at room temperature, methanol was distilled off. The residue was applied to a silica gel column chromatography and the product was eluted with a mixed solvent of chloroform and methanol (9:1 by volume ratio) to provide 2.4 g of 5-{2-[2-(2-methoxyphenoxy)-ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide as a viscous oily material.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:13][CH2:14][C:15]3[NH:22][C:20](=[O:21])[C:19]4[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: NC(=O)c1ccccc1NC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(CCn2cnc(-c3ccccc3)c2)nc2ccccc12
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A solution of 4-phenyl-1H-imidazole (500 mg, 3.47 mmol), 2-(3-chloropropanamido)benzamide (1.17 g, 5.21 mmol) and K2CO3 (717 mg, 5.20 mmol) in DMF (50 mL) was stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting product was washed with EtOAc and filtered to give the desired product (60 mg). LC-MS: m/z 317 (M+H+).
Reaction SMILES: [NH2:1][CH2:2]/[CH:3]=[CH:4]/[CH:5]=[CH2:6].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1>>[OH:10][CH2:11][CH:7]1[CH2:6][CH:5]=[CH:4][CH:3]2[CH:8]1[CH2:9][NH:1][CH2:2]2
Reactant: C1CCOC1
Reactant: C=C/C=C/CN
Product: OCC1CC=CC2CNCC21

Procedure:
Initially introduce 83.2 g (1.0 mol) of (E)-1-amino-2,4-pentadiene (title compound from Example B.2.) in 250 ml of THF, and add 0.1 g of 4-hydroxyanisole. Subsequently, at an internal temperature of 20°-30° C., add 229.2 g (1.05 mol) of di-tert-butyl dicarbonate dissolved in 250 ml of THF dropwise. After addition is complete, stir at room temperature for 20 h. Add 103.0 g (1.05 mol) of maleic anhydride, and heat to reflux for 5 h. Concentrate and take up the residue in 500 ml of methanol, add 30 ml of p-toluenesulphonic acid, and then heat once again to reflux for 5 h. After cooling with ice, and stirring, rapidly add a solution of 20 g of sodium carbonate dissolved in 500 ml of water dropwise, allow the mixture to stand for a further 30 min in an ice bath, and filter off the precipitate with suction, wash it with a little water, and dry it at 50° C. to constant weight.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:16].[CH3:25][C:26]1[N:27]=[C:28]([N:41]2[C:45](=[O:46])[NH:44][N:43]=[CH:42]2)[S:29][C:30]=1[C:31]([NH:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:32]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][N:44]2[C:45](=[O:46])[N:41]([C:28]3[S:29][C:30]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[C:26]([CH3:25])[N:27]=3)[CH:42]=[N:43]2)=[CH:19][CH:20]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2cnn(CC(=O)Nc3ccc(Cl)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 2-bromo-N-(4-chlorophenyl)acetamide to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 25% yield: mp 255-256° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.90 (t, J=5.8 Hz, 1H), 8.79 (s, 1H), 8.52 (br s, 1H), 8.44 (br s, 1H), 7.75-7.65 (m, 1H), 7.61-7.49 (m, 2H), 7.39-7.28 (m, 3H), 4.67 (s, 2H), 4.40 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 484.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[CH:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Reactant: CC(C)Br
Product: CC(C)Oc1c(Br)cc(Br)c2cccnc12
Yield: 97 %

Procedure:
Reaction of 5,7-dibromo-quinolin-8-ol with 2-bromopropane following the method described in Example 8 gave 5,7-dibromo-8-isopropoxy-quinoline 6 (97%): 1H NMR (CDCl3): δ 8.94 (dd, J=1.5 and 4.2, 1 H), 8.48 (dd, J=1.5 and 8.4, 1 H), 8.00 (s, 1 H), 7.52 (dd, J=4.2 and 8.4, 1 H), 5.22 (m, 1 H), 1.43 (d, J=6.1, 6 H); mass spectrum: m/z 344, 346, 348 (M++1, 50, 100 and 50%, respectively). Reaction of 6 with aryl boronic acids, and cleavage of the isopropoxy group following the method outlined in Example 8 gave compounds L1 and L2 (data in Table 4).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>>[OH:8][CH2:7][CH2:6][N:5]1[CH2:2][CH2:1][O:4][CH2:9][CH2:10]1.[O:8]1[CH2:9][CH2:10][N:5]([CH:6]([N:5]2[CH2:2][CH2:1][O:4][CH2:9][CH2:10]2)[CH3:7])[CH2:6][CH2:7]1
Reactant: OCCO
Reactant: C1COCCN1
Product: CC(N1CCOCC1)N1CCOCC1
Product: OCCN1CCOCC1
Temperature: 180 °C
Yield: 3 %
Yield: 93 %

Procedure:
A 22 ml stainless steel Parr bomb reactor was charged with 5.5 g ethylene glycol (88.6 mol), 1.01 g morpholine (11.5 mol), 130 mg RuCl3 (PPh3)3 (1.3×10-4 mol) 250 mg PPh3 (9.5×10-4 mol) 0.52 g N-methylpyrrolidinone (as internal standard) and a magnetic stirring bar in a nitrogen-filled glove box. The bomb was sealed and placed in a previously-heated oil bath with stirring. After heating for 2.5 h at 180° C., the reactor pressure was 44 psig. At this point, the bomb was cooled to room temperature at which point the pressure stood at 17 psig. The reactor was vented, opened and the contents analyzed by GLC. The analysis showed that all of the morpholine had reacted to give 1.42 g hydroxyethylmorpholine (93% yield) and 0.04 g bismorpholinoethane (3% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH2:9][NH2:10]>>[FH:1].[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][NH2:10])=[N:3][CH:4]=1
Reactant: NN
Reactant: Fc1ccc(F)nc1
Product: F
Product: NNc1ccc(F)cn1
Temperature: 120 °C
Yield: 45.3 %

Procedure:
To 2,5-difluoropyridine (3 g, 26.1 mmol) was added hydrazine (1.636 ml, 52.1 mmol) and the contents were heated in a microwave at 120° C. for 1 h. Upon cooling, a white solid formed. The solid was collected by filtration, washed with ether and dried in vacuo to give 1.74 g of 5-fluoro-2-hydrazinylpyridine, hydrofluoride that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (1H, d, J=2.86 Hz), 7.42 (1H, td, J=8.80, 2.86 Hz), 7.35 (1H, br. s.), 6.73 (1H, dd, J=9.02, 3.74 Hz), 4.12 (2H, br. s.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)nc1C
Yield: 29.4 %

Procedure:
Using (4-iodophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 120 and isothiazolidine 1,1-dioxide (121 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (126 mg) was obtained.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11].O>CO>[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1c(F)cncc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(F)cncc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of sodium borohydride (198 mg, 5.2 mmol) in anhydrous methanol (8 mL) was added a solution of 3,5-difluoropyridine-4-carbaldehyde (0.5 g, 3.5 mmol) in anhydrous methanol (2 mL) at 0° C. The mixture was stirred for 6 hours at room temperature. Water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3,5-difluoropyridin-4-yl)methanol was obtained and used in the next step without purification; 1H NMR (400 MHz, CDCl3): δ 2.25 (bs, 1H), 4.85 (s, 2H), 8.36 (s, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH2:7][CH2:6]2.[CH3:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)=[O:15].Cl.C1C2C(=CC=CC=2)CCN=1.C(C(C1CCCCC=1)=O)C>>[CH3:2][C:3]1[CH:12]=[CH:11][C:10]2[CH:9]3[N:8]([CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[C:14](=[O:15])[CH2:13]3
Reactant: Cc1ccc2c(c1)CCN=C2
Reactant: CC(=O)C1=CCCCC1
Agent: C1=NCCc2ccccc21
Agent: CCC(=O)C1=CCCCC1
Agent: Cl
Product: Cc1ccc2c(c1)CCN1C2CC(=O)C2CCCCC21

Procedure:
when in Example 1 an appropriate amount of 3,4-dihydro-6-methylisoquinoline hydrochloride and 1-cyclohexen-1-yl methyl ketone are substituted for 3,4-dihydroisoquinoline hydrochloride and 1-cyclohexen-1-yl ethyl ketone respectively, 2,3,4,4a,6,7,11b,12,13,13a-decahydro-9-methyl-1H-dibenzo[a,f]quinolizin-13-one is obtained, M.P. 101°-121°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:28])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 41.1 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (765 mg) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (991 mg), 2-amino-6-(trifluoromethyl)benzothiazole (1.0 g), 1,1′-thiocarbonyldiimidazole (1.09 g), and EDC (1.32 g). LC/MS: m/z 407.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.15 (s, 1H), 7.97 (d, 1H), 7.95 (d, 1H), 7.85 (d, 1H), 7.62-7.43 (m, 2H), 3.86 (s, 3H), 3.62 (bs, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.N1([C:23](=[O:31])[CH2:24][CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][O:27]2)C=CN=C1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH2:25][CH2:24][C:23]([CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][O:11][CH2:12]1)=[O:31]
Reactant: O=C1CCOCC1
Reactant: O=C(CCC1CCCO1)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1CCOCC1C(=O)CCC1CCCO1
Reaction time: 0.03 h
Yield: 15.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.283 ml, 6.83 mmol) was added to a stirred solution of tetrahydro-4H-pyran-4-one (0.601 ml, 6.51 mmol) in toluene (3 mL) at 0° C. and the resulting mixture was stirred for 2 minutes. 1-(1H-imidazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (0.632 g, 3.25 mmol) toluene (1 mL) was added and the reaction mixture was stirred for 5 minutes before it was quenched with acetic acid (0.559 ml, 9.76 mmol) in water (4 mL). The organic layer was separated and purified by flash column chromatography (ethyl acetate in heptane, 0 to 40%) yielding 3-(3-(tetrahydrofuran-2-yl)propanoyl)dihydro-2H-pyran-4(3H)-one (117 mg, 16%).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12].[C:22]([CH2:24][C:25](OCC)=[O:26])#[N:23].C(=O)([O-])[O-].[K+].[K+]>CCO>[C:22]([C:24]1[C:17]([C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)=[N:10][C:8]([S:7][CH3:6])=[N:9][C:25]=1[OH:26])#[N:23]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CSC(=N)N
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CSc1nc(O)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Temperature: 0 °C

Procedure:
A mixture of S-methylisothiourea sulfate (69.0 g), 3-nitrobenzaldehyde (75.0 g), ethyl cyanoacetate (56.0 ml) and potassium carbonate (72.5 g) in abs. EtOH (1500 ml) was stirred at 60° C. for 16 h. The reaction mixture was cooled to 0° C. in an ice bath. The resulting precipitate was filtered off, washed with abs. EtOH and dissolved in hot water (100° C.). The solution was cooled to room temperature, acidified with 2N HCl to pH 2 and cooled to 0° C. in an ice bath. The resulting precipitate was filtered off and washed with ice water. Residual water in the precipitate was removed by coevaporation with 1,4-dioxane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].CI.[OH-].[C:12]([OH:24])(=[O:23])[CH2:13][C:14]([CH2:19][C:20]([OH:22])=[O:21])([C:16]([OH:18])=[O:17])[OH:15]>>[C:12]([O-:24])(=[O:23])[CH2:13][C:14]([CH2:19][C:20]([O-:22])=[O:21])([C:16]([O-:18])=[O:17])[OH:15].[CH3:12][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[CH3:12][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[CH3:12][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8]
Reactant: Cc1cccnc1C
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [OH-]
Solvent: CI
Product: Cc1ccc[n+](C)c1C
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
2-3-Lutidine is reacted with methyl iodide; the halide intermediate is converted to the hydroxide with Rexyn 201, and then reacted with citric acid.