Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24].C(O)(=O)C(O)=O>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CC(C)CBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CC(C)CN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 51. Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (6 mL), potassium carbonate (0.25 g, 1.84 mmol), 1-bromo-2-methylpropane (0.1 mL, 0.92 mmol). Flash chromatography on silica gel (ethyl acetate/methanol, 9:1). Yield: 0.18 g. [α]D=+22.6° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 164-165° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 2), 212 (bp), 182 (46), 213 (12), 127 (8), 98 (6) 1-bromo-2-methylpropane.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: Nc1ccccn1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(C)O3)nc2ccccn12
Yield: 48.5 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.05 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.2 g) and 2-aminopyridine (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[C:19][Si](C)(C)C)[C:15]([CH3:24])=[N:14]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[CH:19])[C:15]([CH3:24])=[N:14]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl4-trimethylsilylethynylpyrazole (0.82 g) in methanol (15 ml) was added potassium carbonate (0.75 g). After 3 hours at room temperature the reaction mixture was poured into water (100 ml) and extracted with ether (50 ml, ×2). The combined organic layers were washed with brine, dried and evaporated to provide the title compound as a light beige gum.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][S:7][C:8]1[C:17]([CH3:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:23][N:3]([CH3:2])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][S:7]([C:8]1[C:17]([CH3:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:32]
Reactant: Cc1nc2ccccc2nc1SCc1ccccc1N(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2ccccc2nc1S(=O)Cc1ccccc1N(C)C
Yield: 31.3 %

Procedure:
In a mixture of 10 ml of chloroform and 10 ml of methanol was dissolved 1.73 g of 2-(2-dimethylaminobenzylthio)-3-methylquinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was portionwise added 1.14 g of m-chloroperbenzoic acid (purity: 80%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), and recrystallized from ethyl acetate/hexane to give 0.51 g of 2-(2-dimethylaminobenzylsulfinyl)-3-methylquinoxaline as a pale brown crystalline powder, m.p. 68°-70° C. (decompn.).
Reaction SMILES: [Na].[C:2]1([SH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S[C:12]([CH3:22])([CH3:21])[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])C>C(O)C>[C:2]1([S:8][C:12]([CH3:21])([CH3:22])[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)(C)Sc1ccccc1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a solution of 11.5 g of metallic sodium dissolved in 250 ml of ethanol, 55 g of thiophenol was added, and then ethanol was distilled off. After adding 400 ml of formamide to the residue to form a uniform solution, the solution was immersed in an ice bath, and to the solution 119 g of ethyl (2-ethylthio2-methylpropionyl)acetate was gradually added. After the completion of the addition, the reaction mixture was removed from the ice bath and stirred for three hours. The reaction mixture was poured into one liter of water and extracted twice, each time with 800 ml of diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution and dried with anhydrous sodium carbonate. After distilling off the diethyl ether, the residue was recrystallized from n-hexane to obtain 112 g (yield 84%) of the intended compound having a melting point of 44° to 45° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2s1
Reactant: C1CNCCN1
Product: c1ccc2sc(N3CCNCC3)nc2c1

Procedure:
2-Chlorobenzothiazole (5.00 g), is heated in alcohol (75 ml) with 3.05 g piperazine (3.05 g) for 20 hr. The mixture is partitioned between methylene chloride/ether and aqueous sodium bicarbonate, the phases are separated, the organic phase is dried with sodium sulfate and concentrated to give 2-piperazinobenzothiazole which is reacted at 70° in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (7.45 g) and potassium carbonate (2.44 g) for 6 hr and at 20°-25° for 3 days. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated, the organic phase is dried with sodium sulfate and concentrated. The concentrate is chromatographed on silica gel eluting with methanol/methylene chloride (6/94) to give the title compound which is recrystallized from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][NH:25][CH:22]([CH3:24])[CH3:23])[CH2:7][CH2:6][CH2:5]2
Reactant: CC(C)N
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)NCCN1CCCc2cc(Br)ccc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 1, 0.400 g, 1.093 mmol) in acetonitrile (19 mL) and water (1 mL) in a 50 mL pressure vessel fitted with a stir-bar was treated with potassium carbonate (0.755 g, 5.46 mmol) and isopropylamine (0.646 g, 10.93 mmol) and the sealed vessel stirred at 75° C. overnight. After 24 hours the mixture was partitioned between CH2Cl2 (50 mL) and water (10 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer (pH=12); extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to a yellow oil. Purification on silica gel eluting with 5% 2M NH3 in methanol/95% dichloromethane yielded a pale yellow oil, 2 (270 mg, 83%). 1H-NMR (DMSO-d6) δ 7.06 (dd, 1H, J=8.8, 2.5 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.52 (d, 1H, J=8.8), 3.31-3.20 (m, 4H), 2.78-2.67 (m, 1H), 2.67-2.59 (m, 4H), 1.84-1.76 (m, 2H), 0.96 (d, 6H, J=6.2 Hz). MS (ESI+): 297/299 (MH+, 10), 238/240 (20), 159 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C:11]([CH3:23])([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:24])[N:4]=[C:3]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].N#N.[H][H]>C1COCC1.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:33])([CH3:1])[C:3]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[N:4][C@:5]3([CH3:24])[C:14]=2[CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C

Procedure:
Solution of tert-butyl ((4aR,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (56 mg, 0.116 mmol) in THF (1.1 ml) was purged with N2, and hydrogenated under hydrogen balloon in the presence of palladium 10 wt. % Pd on activated carbon (37.1 mg, 0.035 mmol) for 4.5 h. The mixture was filtered through the plug of Celite, and the filter cake was washed with ethyl acetate. The combined filtrate was concentrated to afford the crude tert-butyl ((4aR,11bR)-10-amino-3,3,6,6,11b-pentamethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate which was used for next step directly. MS m/z=452.1 (M+H).
Reaction SMILES: C(O[C:6]([N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)=O)(C)(C)C.C=O>C(O)(=O)C>[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:8]2[CH2:9][CH2:10][CH2:11][C:12]3[CH:16]=[CH:15][O:14][C:13]=3[CH2:6]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCCc1ccccc1)CCCc1ccoc1
Agent: C=O
Solvent: CC(=O)O
Product: c1ccc(CCCCCCN2CCCc3ccoc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of the above crude N-[3-(3-furyl)propyl]-6-phenylhexylamine in 100 ml of acetic acid, 0.74 g (9.1 mmol) of 37% aqueous formaldehyde was added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 3/1) to yield the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]=[N:13][CH:14]([C:24]([CH3:26])=[O:25])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]=[N:13][CH:14]([C:24]([CH3:26])=[O:25])[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])(=[O:29])[CH3:28]
Reactant: CC(=O)C(N=Nc1cc(S(=O)(=O)O)ccc1O)C(=O)Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)O)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1

Procedure:
α-(2-hydroxy-5-sulfophenylazo)acetoacetanilide (40 g) was dissolved in boiling pyridine (750 ml) and acetic anhydride (100 ml) added. Some material precipitated while the reaction mixture was hot. After being cooled, the product was filtered off and dried. Yield: 38 g.
Reaction SMILES: [O:1]=[S:2]1(=[O:52])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:45])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20](/[CH:33]=[CH:34]/[C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1.CO>[O:52]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:45])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20](/[CH:33]=[CH:34]/[C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a solution of methyl 4-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)vinyl)benzoate (35 mg, 0.048 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 50° C. for 2 h. The crude product was purified by prep HPLC (method 4) to give 4-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)vinyl)benzoic acid as a white solid (12 mg, 35.0%). MS: m/e 717.5 (M+H)+, 2.798 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.08-7.95 (m, 2H), 7.47 (br. s., 2H), 6.98-6.83 (m, 1H), 6.77-6.64 (m, 1H), 5.87 (d, J=4.8 Hz, 1H), 4.72 (br. s., 1H), 4.61 (br. s., 1H), 3.27-3.06 (m, 8H), 2.95 (d, J=7.3 Hz, 2H), 2.86-2.62 (m, 3H), 2.23-2.00 (m, 3H), 1.98-1.79 (m, 4H), 1.73 (br. s., 3H), 1.66-1.50 (m, 5H), 1.48-1.18 (m, 10H), 1.11 (s, 3H), 1.09-1.05 (m, 3H), 1.03-0.96 (m, 6H), 0.76 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)=[CH:14][CH:13]=1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:36]1([NH:46]N)[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:37]4[C:36](=[C:45]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]5=[CH:39][CH:38]=4)[NH:46][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:28])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(NS(C)(=O)=O)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
1-tert-Butoxycarbonyl-4-[4-(methylsulfonyl)aminobenzyl]piperidine (1.4 g, 3.81 mmol) was dissolved in N,N-dimethylformamide (10 mL). To the solution was added 72% sodium hydride in mineral oil (143 mg, 4.29 mmol) under ice cooling, and the mixture was stirred for 10 minutes., To the mixture was added methyl iodide (0.25 mL, 4 mmol), and the mixture was stirred at room temperature for 1 hour. After cooling, the reaction mixture was poured into ice-water (20 mL). and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give the titled compound (1.20 g) as colorless powdery crystals.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:5]=1>C(#N)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:2][CH3:1])[CH:7]=[C:6]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:5]=1
Reactant: CN
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Product: CNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylamine (0.382 mL of 33% solution in absolute ethanol, 3.06 mmol) was added to a solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (200 mg, 0.77 mmol) in acetonitrile (3 mL). The mixture was stirred at ambient temperature for 30 minutes. The solvents was removed in vacuum, and the residue was purified by preparative HPLC to yield the title compound, 135 mg, (69%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[C:15]1([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(NC3CCNCC3)nccc2c1

Procedure:
A solution of 4-(isoquinolin-1-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.83 g, 2.54 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 228.6 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:27]([NH:26][CH2:3][C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:5]=2)=[O:28])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Agent: Cl
Product: O=C(NCc1ccccc1)N1CC(OC(c2ccc(Cl)cc2)c2ccc(F)cc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzydryloxy]azetidine hydrochloride (125) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccccc2C(C)=O)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
2′-Fluoroacetophenone (10.6 g), methyl 4-hydroxybenzoate (11.7 g) and potassium carbonate (11.2 g) were suspended in dimethylacetamide (70 ml), and the mixture was stirred at 140° C. for one day. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give the title compound (8.62 g).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH:10]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11]1>C(#N)C>[CH:10]1([NH:13][C:14]([N:6]2[CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:5]2)=[S:15])[CH2:12][CH2:11]1
Reactant: c1nc2c([nH]1)CCNC2
Reactant: S=C=NC1CC1
Solvent: CC#N
Product: S=C(NC1CC1)N1CCc2[nH]cnc2C1
Yield: 32 %

Procedure:
A solution of 2.462 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2.97 g of cyclopropyl isothiocyanate in 20 ml of acetonitrile is refluxed for 7 h. After evaporation to dryness, the residue is chromatographed on silica gel (ethyl acetateethanol as eluant) to give 1.42 g of the pure title compound, m.p. 185°.
Reaction SMILES: [C:1]1([B:11]([OH:13])[OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1B(O)O>>[C:14]1([C:1]2[CH:10]=[CH:5][C:4]([C:4]3[C:3]4[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:1]([B:11]([OH:13])[OH:12])=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[CH:9]4)=[CH:3][CH:2]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: OB(O)c1ccc2ccccc2c1
Product: OB(O)c1c2ccccc2c(-c2ccc(-c3cccc4ccccc34)cc2)c2ccccc12

Procedure:
10-(4-Naphthalene-1-yl-phenyl)anthracene-9-boronic acid was synthesized by the same method, except that in Synthetic Example 1, 1-naphthaleneboronic acid was used as a starting material in place of 2-naphthaleneboronic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1(O)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.C(N(S(F)(F)[F:23])CC)C>C(Cl)Cl>[F:23][C:6]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a −78° C. solution of the product of Example 27A (4.53 g, 17.77 mmol) in methylene chloride (50 mL) was added diethylaminosulfur trifluoride (DAST) (4.18 g, 3.97 mL, 30.0 mmol). The reaction mixture was stirred at −78° C. for four hours, then allowed to warm to ambient temperature, and stirred overnight. The reaction mixture was then cooled to 0° C., quenched with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was separated and concentrated. The resulting residue was chromatographed on silica gel, eluting with 0%-15% ethyl acetate-hexane to obtain the title compound (3.55 g, 78%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.83 (m, 1H), 7.79 (m, 1H), 3.92 (s, 4H), 2.41-2.07 (m, 4H), 1.91-1.63 (m, 4H). MS (DCI) m/z 244 (M+H)+.