Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O>>[F:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(F)c(F)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3,4-difluorobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3,4-difluorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from absolute ethanol/water gave a pale yellow crystalline solid of melting point 270° C. (decomposition).
Reaction SMILES: [C:1]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1.O>C1(C)C=CC=CC=1.CCOCC>[OH:8][C@@H:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2)C1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.9 %

Procedure:
A solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (10.3 g, 35.64 mmol) in anhydrous toluene (120 mL) was cooled to −78° C. and (R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol, 0.5 equiv) was added slowly. After 5 min, catecholborane (11.4 mL, 107 mmol, 3 equiv) was added slowly. The reaction mixture was then transferred into the freezer (−14° C.) and left overnight. LC-MS (16 min) showed a 9:1 ratio of the R to the S isomer. The mixture was cooled to 0° C. and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), and brine (100 mL), and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel column eluted with a 4-35% EtOAc in hexanes gradient. The purified product was recrystallized from an ether/hexanes mixture to afford (R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate (4.45 g, 43%) as a white solid with the ratio of R/S isomers 23.5:1. LC-MS (3 min) tR=1.70 min; LC-MS (3 min) tR=10.62 min, m/z 314 (M+Na). 1H NMR (CDCl3) δ 7.28 (m, 5H), 4.46 (d, 1H), 3.87 (d, 1H), 3.89-3.51 (br s, free exchange 1H), 3.00 (m, 2H), 2.68 (t, 1H), 2.52 (t, 1H), 1.94 (m, 1H), 1.76 (m, 1H), 1.65 (m, 1H), 1.42-1.20 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.Br[CH:15]([CH3:25])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][N:10]([CH:15]([CH3:25])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:9]3)=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)Nc1ccccc1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C(=O)Nc1ccccc1)N1CC2CC2(c2ccc(Cl)cc2)C1
Product: Cl

Procedure:
A mixture of 3.5 g. of (-)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (U.S. Pat. No. 4,131,611), 4.6 g. of 2-bromopropionanilide, 3.7 g. of sodium carbonate and 75 ml. of toluene is stirred and refluxed overnight. The mixture is diluted with 25 ml. of water and 5 ml. of 5 N sodium hydroxide and mixed. The alkaline aqueous layer is extracted with toluene. The toluene layers are combined, washed with water, dried, filtered and concentrated to an oil. The oil is triturated in 50 ml. of ether and filtered. The filtrate is acidified with 6 ml. of 3.55 N alcoholic hydrogen chloride and scratched and resuspended in ether repeatedly until crystalline. The solid is collected, washed with ether, dried, heated to solution in 25 ml. of acetonitrile, filtered and cooled, giving 1.2 g. of the desired product, m.p. 227°-228° C.
Reaction SMILES: C(OC(=O)C[N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([NH:9][CH:10]1[CH:17]2CC3CC(CC1C3)C2)=[O:8])C.[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[CH2:36]([Al+]CC(C)C)[CH:37](C)[CH3:38]>C(Cl)Cl>[CH:28]12[CH2:34][CH:37]3[CH2:38][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH:29]1[N:9]1[CH:10]=[CH:17][N:6]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:7]1=[O:8])[CH2:33]2
Reactant: Cc1ccccc1
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Agent: [H-]
Solvent: ClCCl
Product: O=c1n(Cc2ccccc2)ccn1C1C2CC3CC(C2)CC1C3
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(3-Adamantan-2-yl-1-benzyl-ureido)-acetic acid ethyl ester (450 mg) was dissolved in dry DCM (5 mL) and toluene (5 mL) under argon and cooled to −78° C. Diisobutylaluminium hydride (1 M solution in DCM, 1.46 mL) was added drop by drop over 5 minutes and the mixture was allowed to stir at −78° C. for 30 minutes. The cooling bath was removed and after 10 minutes, the reaction mixture was quenched by addition of aqueous potassium sodium tartrate solution (1M, 15 mL). The mixture was extracted with chloroform twice and the combined organic extracts were washed with brine. The combined organic layers were shaken with 25% HCl (30 mL) for 5 minutes and the layers were separated. The organic solution was dried with sodium sulfate, filtered and evaporated to give a crude product that was purified by flash chromatography using a gradient of 20% to 80% ethyl acetate in heptane as an eluent. The fractions containing the product were combined and evaporated to give 1-adamantan-2-yl-3-benzyl-1,3-dihydro-imidazol-2-one as a white solid (276 mg). MS (EI): 308.2 (M+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].OC1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[C:17](=O)([O-])[O-:18].[K+].[K+]>CC(C)=O>[CH2:15]([C:12]1[CH:11]=[CH:10][C:7]([CH:17]=[O:18])=[C:6]([O:5][C:3](=[O:4])[CH3:2])[CH:13]=1)[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(C=O)c(OC(C)=O)c1

Procedure:
4-Ethyl acetoxy benzaldehyde was prepared by the reaction of one mole of ethyl bromoacetate with one mole of 4-hydroxy benzaldehyde in the presence of one mole of anhydrous Potassium Carbonate in refluxing acetone. This precursor material was vacuum distilled after filtration and concentration of the reaction mixture. The precursor boiled in the range 138°-140° C. at 0.2 mbar and appeared as a slightly yellowish liquid which crystallized on standing.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=S)=[CH:5][CH:4]=1.[F:14][C:15]([F:38])([F:37])[C:16]1[NH:20][C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:29]=[C:30]([NH2:36])[C:31]([NH:34][CH3:35])=[CH:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)=[N:18][CH:17]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(#N)C.O>[CH3:35][N:34]1[C:31]2[CH:32]=[CH:33][C:28]([O:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([C:19]4[NH:20][C:16]([C:15]([F:37])([F:14])[F:38])=[CH:17][N:18]=4)[CH:26]=3)=[CH:29][C:30]=2[N:36]=[C:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: CNc1ccc(Oc2ccnc(-c3ncc(C(F)(F)F)[nH]3)c2)cc1N
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cn1c(Nc2ccc(C(F)(F)F)cc2)nc2cc(Oc3ccnc(-c4ncc(C(F)(F)F)[nH]4)c3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
4-Trifluoromethylphenyl isothiocyanate (200 mg, 1 mmol) was added to a mixture of 4-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N1-methylbenzene-1,2-diamine (350 mg, 1 mmol) in 3 mL of acetonitrile. After stirring for 20 min at ambient temperature, HPLC analysis showed complete conversion. Triethylamine (0.3 mL, 2.2 mmol) was added followed by 2-chloro-1-methylpyridinium iodide (270 mg, 1.05 mmol). The reaction mixture was heated to 50° C. for 5 h. The heating was stopped and 1.5 mL of water was added. After stirring the mixture for 2 h, the solid was collected by filtration and washed with 2:1 acetonitrile/water (3×1 mL) to afford 317 mg (61%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](OC)=[O:20])=[CH:18][C:13]=3[O:12][CH:11]=2)[CH2:5]1.Cl.O>O1CCCC1>[OH:20][CH2:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:11][O:12][C:13]=2[CH:18]=1
Reactant: COC[C@H]1CN(c2coc3cc(C(=O)OC)ccc23)C(=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H]1CN(c2coc3cc(CO)ccc23)C(=O)O1
Temperature: 55 °C

Procedure:
22 ml of a 2M solution (0.044 mol) of a borane-dimethyl sulphide complex in tetrahydrofuran are added, in two steps, to a solution of 3.3 g (0.011 mol) of methyl (R)-3-[5-(methoxymethyl)-2-oxooxazolidin-3-yl]benzofuran-6-carboxylate in 40 ml of tetrahydrofuran and the mixture is heated for five hours at 55° C. The mixture is hydrolysed with 1N hydrochloric acid. The mixture is poured into water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product is purified by chromatography on silica gel with a 99/1 mixture of dichloromethane and methanol. After crystallization from ethyl ether, 2.0 g of product are recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33]SC(C)C)[CH:14]([N:16]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]3=[O:32])[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:39][S:40]([O-:42])=O.[K+].C(OCC)(=O)C.[CH:50](O)([CH3:52])[CH3:51]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][S:40]([CH:50]([CH3:52])[CH3:51])(=[O:42])=[O:39])[CH:14]([N:16]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]3=[O:32])[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)SCC1C2CN(C(=O)OC(C)(C)C)CC2CC1N1CCC(NC(=O)OCc2ccccc2)C1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)CC1C2CN(C(=O)OC(C)(C)C)CC2CC1N1CCC(NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A solution of 5-(3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-4-isopropylsulfanylmethyloctahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester in isopropanol is treated with a solution of oxone in water. The reaction mixture is stirred at room temperature until the reaction is complete, and then water and ethyl acetate are added. The organic layer is separated, dried over sodium sulfate and concentrated under vacuum providing the title product.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:19][NH2:20].O.ClCCl>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:10]2[S:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:20][CH3:19])=[N:7][CH:6]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: COc1ccc2sc(-c3ccc(F)nc3)nc2c1
Reactant: CN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1
Temperature: 100 °C

Procedure:
To 2-(6-fluoropyridin-3-yl)-5-methoxy-1,3-benzothiazole (59.2 mg, 0.227 mmol) was added methylamine in ethanol (8 M, 2 mL) and the reaction mixture was heated in a microwave oven at 100° C. for 5 min. Water and dichloromethane were added and the layers separated. The aqueous phase was extracted with dichloromethane (3×). The combined organic phases were washed with water, dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by column chromatography (heptane/EtOAc 60:40 to 50:50) to give the title compound (39 mg) as a pale yellow solid. 1H NMR δ ppm 8.68 (d, 1H) 7.98 (dd, 1H) 7.91 (d, 1H) 7.50 (d, 1H) 7.27 (q, 1H) 7.01 (dd, 1H) 6.59 (d, 1H) 3.85 (s, 3H) 2.86 (d, 3H); MS m/z (M+H) 272.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][CH3:21])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(COC)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a mixture of (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.18 g, 0.64 mmol) and K2CO3 (0.44 g, 3.2 mmol) in acetone was added Me2SO4 (0.16 g, 1.28 mmol). The mixture was stirred at room temperature for 16 hours then diluted with EtOAc. The organic extracts were washed with HCl (aq), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give (1-hydroxy-6-methoxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.060 g, 32%). 1H NMR (400 MHz, MeOD-d4) δ 7.08 (s, 1H), 6.99 (s, 1H), 5.62 (m, 1H), 5.50 (m, 2H), 4.08 (m, 2H), 3.80 (s, 3H), 3.37 (s, 3H), 3.12 (m, 1H), 2.17 (m, 1H), 1.20 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:43]=[CH:42][C:29]([CH2:30][N:31]3[C:39](=[O:40])[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:41])=[CH:28][CH:27]=2)[O:21][N:20]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][S:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[N:23]=[C:22]([CH2:24][O:25][C:26]3[CH:43]=[CH:42][C:29]([CH2:30][N:31]4[C:32](=[O:41])[C:33]5[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:39]4=[O:40])=[CH:28][CH:27]=3)[O:21][N:20]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3)no2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)CC3CCCCC3)no2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
Cyclohexylmethanesulfonyl chloride (359 mg) [King. J. F. et al., J. Am. Chem. Soc., 1992, 114(5), 1743-9] was added to a solution of 2-[4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione hydrochloride (627 mg) [see Preparation 153 and triethylamine (0.4 ml) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 18 hours after which time it was heated to 30° C. and stirred for a further 56 hours. The mixture was diluted with dichloromethane and washed with dilute aqueous hydrochloric acid solution, the organic layer dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 75:25, by volume, hexane:ethyl acetate to afford 2-[4-(3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione (192 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.[F:21][P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:48][NH:49][CH:50]([CH:52](F)[CH3:53])[CH3:51].CCN(CC)CC>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:49]([CH3:48])[CH:50]([CH2:52][CH2:53][F:21])[CH3:51])=[O:20])[N:9]=1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CNC(C)C(C)F
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2I)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CCF)N(C)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.2 %

Procedure:
To a solution of 1-(2-iodophenyl)-3-isoquinolinecarboxylic acid (54.4 mg, 0.15 mmol), BOP (65.4 mg, 0.15 mmol) in DMF (6 mL) under Ar was added a solution of N-methyl 3-fluoro-2-butylamine (333.3 mg, crude, excess) and Et3N (21 μL, 0.15 mmol) in DMF (1.0 mL). The resulting mixture was stirred at ambient temperature for 7 h. Then it was quenched by adding H,O (5 mL). The mixture was extracted with CH2Cl2 (3×20 mL). The organic layers were dried (Na2SO4), filtered. The filtrate was concentrated in vacuo. The residue was purified on column chromatography (silica gel, 30% ethyl acetate/hexane, 0.05% Et3N) to give a yellow oil (36.2 mg). This oil was further purified on reverse phase HPLC (75% MeOH/H2O, 0.1% Et3N). Two major fractions were collected. The first fraction (Rt=13 min, 12 mg, 17%) was the title compound. mp 62-63.5° C. 1H NMR (CDCl3) d 1.20-1.40 (m, 3 H, CH3), 1.72-2.30 (m, 2 H, CH2), 3.01, 3.02 (two s, total 3 H, N-methyl), 4.32-4.57 (m, 2 H, CH2F), 4.60-4.71 (m, 0.5 H, CH), 4.92-5.02 (m, 0.5 H, CH), 7.21 (t, J=7.2 Hz, 1 H, aromatic), 7.32 (d, J=7.8 Hz, 1 H, aromatic), 7.46-7.64 (m, 3 H, aromatic), 7.72-7.83 (m, 1 H, aromatic), 7.95-8-19 (m, 3 H, aromatic). HRMS Cacld for C21H20FIN2O: 462.0604. Found: 462.0598.
Reaction SMILES: O=C1C2CC3(C(O)=O)CC(CC1C3)C2.C(Cl)(=O)C(Cl)=O.O.[NH3:22].O=[C:24]1[CH:31]2[CH2:32][C:27]3([C:34]([NH2:36])=[O:35])[CH2:28][CH:29]([CH2:33][CH:25]1[CH2:26]3)[CH2:30]2.N.[H][H]>>[NH2:22][CH:24]1[CH:31]2[CH2:32][C:27]3([C:34]([NH2:36])=[O:35])[CH2:28][CH:29]([CH2:33][CH:25]1[CH2:26]3)[CH2:30]2
Reactant: N
Reactant: NC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Reactant: [H][H]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Solvent: O
Product: NC(=O)C12CC3CC(C1)C(N)C(C3)C2

Procedure:
More detailed explanations on Reaction Formula 1 are as follows: 4-oxoadamantane-1-carboxylic acid (1) is treated with oxalic chloride and ammonia water to prepare 4-oxoadamantane-1-carboxylic acid amide (2), and the resulting compound is treated with ammonia and subjected to a reduction reaction by using hydrogen to produce 4-aminoadamantane-1-carboxylic acid amide (3). 4-aminoadamantane-1-carboxylic acid amide thus prepared is a mixture of (E) and (Z) types, which is made into a salt form by using hydrochloric acid and then subjected to recrystallization by using acetonitrile and water to yield a pure (E) type of 4-aminoadamantane-1-carboxylic acid amide (4).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[I:7][CH2:8][CH3:9]>>[I-:7].[CH2:5]([N+:4]1[CH:9]=[CH:8][N:2]([CH3:1])[CH:3]=1)[CH3:6]
Reactant: Cn1ccnc1
Reactant: CCI
Product: CC[n+]1ccn(C)c1
Product: [I-]
Reaction time: 48 h

Procedure:
200 mmol of 1-methylimidazole was taken in a round bottom flask and sealed with a rubber septum. To this, 100 mmol of iodoethane were added drop-wise over a period of one hour using a syringe. The contents in the flask began to bubble rapidly and turned light yellowish in color. The reaction flask was deoxygenated with dry nitrogen gas for about 15 min. The reaction was carried out at 80° C. for 2 days, under an inert nitrogen atmosphere. The contents were then precipitated drop-wise in cold diethyl ether and a white powder settled down. The ether phase was decanted and the contents were dissolved in chloroform, reprecipitated in ether several times, filtered, and dried in a vacuum oven at 50° C. The final product was a light yellowish powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[OH-].[Na+]>C(O)C.O>[NH2:19][CH2:18][CH2:17][CH2:16][NH:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:27][O:28][CH2:29][CH3:30]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of tert-butyl {3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.30 g, 3.14 mmol) in 10 mL of ethanol was treated with a solution of 3 M hydrogen chloride in ethanol (5.0 mL, 15 mmol) and heated to 100° C. After 30 min, the solvent was concentrated under reduced pressure to yield a brown sludge. The material was triturated with diethyl ether and filtered to give a tan solid. The solid was dissolved in water and treated with 10% NaOH solution until pH 13 was reached. The aqueous solution was extracted with CH2Cl2 (4×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.77 g) as a gold colored foam.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2nsnc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: BrCc1cccc2nsnc12

Procedure:
A mixture of 4-methyl-2,1,3-benzothiadiazole (6.0 g, 40 mmol) and N-bromosuccinimide (7.12 g, 40 mmol) in carbon tetrachloride (80 mL) was refluxed under irradiation with a sunlamp for 8 hours. After cooling with ice-water bath, the succinimide was filtered off and the filtrate was washed with saturated Na2S2O3, brine, dried over Na2SO4. After removal of solvent pure 4-bromomethyl-2,1,3-benzothiadiazole (8.8 g, 96%) was obtained as a light-yellow crystalline powder. Rf=0.45 (hexane/ethyl acetate=4:1); 1H NMR (200 MHz, CDCl3) δ5.00 (s, 2H), 7.57 (m, 2H), 7.98 (d, J1=8.5 Hz, J2=1.2 Hz, 1H); HRMS: Calcd. for C7H5BrN2S 227.9357, found 227.9395.
Reaction SMILES: [Na].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[CH3:7][C:8]1([CH3:17])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10](=O)[CH2:9]1.O.[CH2:19](OCC)C>>[CH3:7][C:8]1([CH3:17])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([C:3]2[C:2](=[CH2:19])[CH:6]=[CH:5][CH:4]=2)[CH2:9]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: CCOCC
Reactant: C1=CCC=C1
Agent: [Na]
Solvent: O
Product: C=C1C=CC=C1C1CC(C)(C)CC(C)(C)C1
Reaction time: 30 h

Procedure:
Hexane washed sodium spheres (2.40 g, 104 mmol) were slowly added to 100 mL absolute ethanol. The sodium had fully reacted before cyclopentadiene (6.0 mL, 72.6 mmol) and 3,3,5,5-tetramethylcyclohexanone (10.0 mL, 57.1 mmol) were added. After 30 hours, the reaction was poured into 200 mL water and 100 mL diethyl ether were added. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were extracted with water (3×50 mL), dried over MgSO4, filtered, and rotavapped to produce the product in quantitative yield as a yellow oil. MS (GC-MS) m/z 202.3 (M+). 1H NMR (CDCl3): δ 0.97 (s, 12H, CH3), 1.04.(s, 2H, CH2), 2.39 (s, 4H, CH2), 6.52, 6.52 (m, 4H, fulvene-H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2([C:38](O)=[O:39])[CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:38]([C:35]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:37][CH2:36]4)=[O:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Reactant: O=C(O)C1(c2ccccc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)C4(c5ccccc5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-cyclopropanecarboxylic acid.