Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[O-:26][N+:15]1[C:16]2[CH:25]=[C:24]3[C:20](=[CH:19][C:17]=2[N:18]=[C:13]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]2)[N:14]=1)[CH2:21][CH2:22][CH2:23]3
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: N#CC1CCN(CCCN)C1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: N#CC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Yield: 78.1 %

Procedure:
1-(3-Aminopropyl)-3-pyrrolidinecarbonitrile (302) (0.36 g, 2.4 mmol) was added to a stirred solution of chloride 21 (402 mg, 1.8 mmol) and Et3N (0.76 mL, 5.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 56 (476 mg, 78%) as a yellow solid: mp (EtOAc/pet. ether) 111-112° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.72 (br t, J=5.3 Hz, 1H, NH), 3.58 (q, J=6.4 Hz, 2H, CH2N), 2.95-3.07 (m, 6H, H-6, H-8, CH2N), 2.73-2.80 (m, 1H, CHCN), 2.55-2.68 (m, 4H, 2×CH2), 2.23-2.32 (m, 1H, CH2), 2.10-2.18 (m, 3H, CH2, H-7), 1.85 (p, J=6.7 Hz, 2H, CH2); 13C NMR δ 158.7, 154.6, 148.7, 143.3, 129.8, 122.1, 120.6, 114.6, 57.4, 53.3, 52.9, 40.2, 33.1, 32.3, 29.2, 27.7, 26.3, 25.7. Anal. calcd for C18H22N6O: C, 63.9; H, 6.6; N, 24.8. Found: C, 64.0; H, 6.4; N, 24.8%.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14][CH:15]=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[C:19]([CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14][CH:15]=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:20]
Reactant: [C-]#N
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CC#N)O2
Yield: 84.6 %

Procedure:
A solution of N-(2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl)formamide (20 g) and sodium cyanide (17 g) in dimethyl sulfoxide (100 mL) was stirred under argon gas at 100° C. for 13 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/diisopropyl ether to provide 14 g of the title compound. Yield 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:12]3([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:22][CH:23]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: Clc1ccc(-c2ccc(CBr)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccc(Cl)cc4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-4-chlorobiphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.99 (s, 1H), 7.93 (dm, J=9.0 Hz, 2H), 7.45-7.49 (m, 4H), 7.38-7.41 (m, 2H), 7.23-7.26 (m, 2H), 7.06 (dm, J=9.0 Hz, 2H), 3.97, (A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.39 (B of AB, J=13.7 Hz, 1H). MS (m/e): 486.0 & 488.0 (M−H)−Cl isotopes. Anal: Calc for C23H18ClNO5S2.C3H7NO: 55.66% C, 4.49% H, 4.99% N; Found: 55.57% C, 4.41% H, 4.85% N. MP: 197-200° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[CH:31][CH:30]=3)[N:34]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)s1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-[4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine nitrate. Light yellow solid. 1H-NMR (CDCl3), δ: 2.37 (s, 3H, CH3), 2.61 (m, 4H, CH2), 2.69 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.20 (m, 4H, CH2), 6.88 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.94 (s, 1H, NH), 6.96 (d, 2H, J=8.8 Hz, Ph-H), 7.51 (d, 2H, J=8.8 Hz, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:18]1([C:22]([C:24]2[CH:25]=[C:26]([Cl:31])[C:27](Cl)=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(N(C)C)=O.O>[N:18]1([C:22]([C:24]2[CH:25]=[C:26]([Cl:31])[C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)OC)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (240 mg, 0.1 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (278 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (5 mL) was stirred at 120° C. for 16 hours. The solution was poured into water (30 mL) and acidified with 1N hydrochloric acid before being extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (as evidenced by LCMS data only m/z 435 (M+H)+) as a brownish oil (550 mg). The crude methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (434 mg, 1 mmol) was dissolved in THF (15 mL) and methanol (5 mL) then 1N aqueous Lithium hydroxide solution (2 mL) added followed by the dropwise addition of water until a clear solution obtained. The mixture was stirred was stirred for 4 hours at RT and the organics removed by evaporation. The aqueous solution was filtered, extracted with ethyl acetate (10 mL) and the aqueous layer acidified with 2N hydrochloric acid. The acidified layer was extracted with ethyl acetate (3×30 mL) and the combined organic extracts washed with water (10 mL), brine (10 mL) and concentrated in vacuo to give the desired compound as a pale oil (375 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 2.32 (quin, 2H), 3.34 (s, 3H), 3.42-3.55 (m, 2H), 4.13-4.34 (m, 4H), 4.54 (q, 1H), 6.93 (s, 1H), 7.40 (s, 1H), 7.48 (s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), m/z 421 (M+H)+
Reaction SMILES: N1C=CC=CC=1.[OH-].[Na+].Cl.C(O)C.[CH3:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([NH2:25])=[O:24])=O)=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)Nc2ccccc2C(N)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Temperature: 0 °C
Yield: 93.1 %

Procedure:
A mixture of 11 ml of pyridine in 340 ml of 2 normal aqueous sodium hydroxide was heated to the reflux temperature and to the hot solution was added in one portion 16.3 g of 2-(4-methylbenzamido)benzamide. The mixture was maintained at reflux temperature for 15 minutes, then poured into 1000 ml of ice. The cold mixture was acidified with concentrated hydrochloric acid and the precipitate was cooled to give 14.1 g of white 2-(4-methylphenyl)-quinazolin-4(3H)-one, m.p. 242°-243.5° (from ethanol).
Reaction SMILES: [C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:42])([CH3:41])[C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[O:29][C@@H:21](OCC[Si](C)(C)C)[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:51])([Cl:50])[Cl:49])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(Cl)[Cl:87]>C(Cl)(Cl)Cl.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:41])([CH3:42])[C:37]([Cl:38])([Cl:40])[Cl:39])=[O:34])[O:29][C@H:21]([Cl:87])[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:50])([Cl:49])[Cl:51])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H](OCC[Si](C)(C)C)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](Cl)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A solution of the compound 8 (6.5 g, 4.84 mmol) and dichloromethyl methyl ether (2.18 ml, 24.2 mmol) in CHCl3 (60 ml) at 0°C. was treated with ZnCl2 (1.0 M in ether; 2.41 ml, 2.41 mmol) and then allowed to warm slowly and stir at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated aq. NaHCO3, dried (Na2SO4) and then concentrated. The light yellow oil obtained was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes to give 5.4 g (88%) of 2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-6-O-(2,2,2-trichloro-1,1-dimethylethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranosyl chloride (compound 9) as an amorphous solid: 1H NMR (CDCl3) δ 0.88 (~t, 6H), 1.1-1.6 (m, 42H), 1.78 (s, 3H), 1.88 (s, 3H), 2.18 (t, 2H, J=7.6 Hz), 2.34-2.52 (m, 2H), 4.2-4.4 (m, 4H), 4.70 (d, 1H, J=12 Hz), 4.73 (d, 1H J=12 Hz), 4.83 (~q, 1H, J=9 Hz), 5.09 (m, 1H), 5.51 (~t, 1H, J=10 Hz), 5.79 (d, 1H, J=8.0 Hz), 6.26 (d, 1H, J=3.6 Hz), 7.1-7.4 (m, 10H).
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH:29]=O.[Cl:39][C:40]1[CH:41]=[C:42]([CH2:47][CH2:48][NH2:49])[CH:43]=[CH:44][C:45]=1[Cl:46].[BH4-].[Na+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]([O:37][CH3:38])([CH3:36])[CH3:35])[CH2:29][NH:49][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][C:45]([Cl:46])=[C:40]([Cl:39])[CH:41]=1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: COC(C)(C)c1ccc(C=O)cc1Cl
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: COC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 77 mg of 3-chloro-4-(1-methoxy-1-methyl-ethyl)-benzaldehyde (0.36 mmol) (described in example S117), 69 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.36 mmol) and 21 mg of sodium borohydride (0.54 mmol). The isolated colorless liquid (126 mg, 90%) was used in the following step without further purification. MS (ISP) 386.1 (M+H)+.
Reaction SMILES: [C:1]12([CH:11](I)[C:12]([OH:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:16][NH2:17]>O1CCCC1>[C:1]12([CH:11]([NH:17][CH3:16])[C:12]([OH:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C(I)C12CC3CC(CC(C3)C1)C2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(C(=O)O)C12CC3CC(CC(C3)C1)C2

Procedure:
Adamantan-1-yl-iodo-acetic acid (7.86 g, 24.55 mmol, P. A. Krasutskii. et. Al. J. Org. Chem. USSR (Engl. Trans.); 1985; 1327-1332) is refluxed with 100 mL of 2M methylamine in tetrahydrofuran for 18 hours. The solvent is evaporated in vacuo, and the residue treated with water. The pH is adjusted to 6 and the resulting solid collected and dried to give 2.16 g of the title compound as a white solid. MS: m/z 224.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:30])[C:17]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:2]1([NH:1][CH:20]2[CH2:19][CH2:18][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([N:16]([CH3:30])[CH3:15])[CH2:22][CH2:21]2)[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1Cc1ccccc1-2
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(Nc2cccc3c2Cc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
1-Aminofluorene (181 mg, 1 mmol) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (1 mmol) and sodium triacetoxyborohydride (300 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 200 mg N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a colorless oil, which, for preparation of the hydrochloride, was dissolved in 2-butanone (5 ml), and 1.85 M ethanolic HCl (0.7 ml) was added. The N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (220 mg, m.p. 223-225° C.).
Reaction SMILES: CCN(CC)CC.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH2:28][C@H:27]1[CH2:30][O:31][C:32]1[CH:33]=[C:34]([C@@H:38]2[CH2:40][C@H:39]2[CH2:41][CH2:42][OH:43])[CH:35]=[N:36][CH:37]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:43][CH2:42][CH2:41][C@@H:39]2[CH2:40][C@H:38]2[C:34]2[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH2:30][C@@H:27]3[CH2:28][CH2:29][N:26]3[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH:33]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@H]2c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-(Dimethylamino)pyridine (DMAP; 14 mg, 0.11 mmol, 0.2 equiv.), Et3N (0.24 mL, 1.7 mmol, 3.0 equiv.), and p-toluenesulfonyl chloride (164 mg, 0.86 mmol, 1.5 equiv.) were added to a stirred solution of 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 0.57 mmol) in dry CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (50 mL). The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by CC (SiO2, 60-70% EtOAc in hexane as the eluent) to give 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethyl p-toluenesulfonate (175 mg, 82%), which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1.[CH2:17]([O:24][C@@H:25]1[C@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:28]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:27][CH:26]1Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]([C@@H:26]2[O:27][C@H:28]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:25]2[O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a mixture of 0.541 g (2.23 mmol) of 2-chloro-5,6-dinitrobenzimidazole in 12 mL of MeCN, was added 0.558 mL (2.23 mmol) of BSA. The reaction mixture was stirred at 75° C. for 15 min to give a clear solution. This solution was treated with the above MeCN solution of 2,3,5-tri-O-benzyl-D-ribofuranosyl chloride and 0.56 mL (2.90 mmol) of TMSOTf at 75° C. for 30 min. The reaction mixture was cooled and diluted with EtOAc (50 mL). The EtOAc solution was washed with sat. NaHCO3 solution (50 mL×2), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (2.2×18 cm, eluted with 20% EtOAc/hexane). Evaporation of fractions 10-14 (20 mL per fraction) gave 0.502 g (35%) of 60 as a syrup. MS: (FAB) m/e 645 (1%, MH+ =645). 1H NMR (DMSO-d6): δ8.50, 8.49 (2×s, 2,7-H and 4-H), 7.34, 6.90 (2×m, 15, 3×Ph), 6.09 (d, 1,1'-H, J1'-2' =8.0 Hz), 4.73~4.27 (m, 9,2'-H, 3'-H, 4'-H, and 3×PhCH2), 3.77 (dd, 1,5'-H, J4'-5' =2.0 Hz, J5'-5" =11.0 Hz), 3.65 (dd, 1,5"-H, J4'-5" =2.5 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3ccccc3n2)cc1

Procedure:
In a manner analogous to that of Example 1(b), but using 4-chloro-2-(4-methylphenyl)quinoline and isonipecotamide as starting materials, the named product was produced, mp. 230°-232° on recrystallization from acetonitrile.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1COCC1.C(Cl)Cl>[Br:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[N:8]=[CH:7]2
Reactant: BrCc1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: BrCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
A yellow suspension of 5-(bromomethyl)-1H-indazole hydrogen bromide (compound 12-4, 3.0 g, 14 mmol) and 3,4-dihydro-2H-pyran (Aldrich, 2.4 g, 29 mmol) in THF (100 mL) was heated at reflux temperature for 2 hours. After cooling down to room temperature, the reaction mixture was stirred at room temperature for 12 hours under nitrogen. The reaction mixture was diluted with methylene chloride (250 mL), washed with saturated aqueous NaHCO3, water and brine. After drying (MgSO4), the solvent was removed under vacuum to give a yellow oil. Flash chromatography yielded the title compound (12-5, 3.34 g, 80%). TLC Rf 0.58 (70:30 hexane-ethyl acetate); MS (electrospray) 295, 297 (M+1); 1H N MR (CDCl3) δ 1.57-1.84 (m, 3H), 2.16 (m, 2H), 2.55 (m, 1H), 3.75 (m, 1H), 4.01 (m, 1H), 4.65 (s, 2H), 5.71 (d, 1H, J=9.2 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(OC(C)C)(C)C>[CH:9](=[N:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: O
Solvent: CC(C)OC(C)C
Product: O[C@@H]1CCCC[C@H]1N=Cc1ccccc1

Procedure:
In a 250 ml round bottom flask equipped with a reflux condenser and a Dean-Stark trap, 6.91 g of racemic trans-2-aminocyclohexanol (60 mmol) obtained according to (b) were dissolved under argon in 70 ml of diisopropyl ether and 6.1 ml of benzaldehyde (60 mmol) were added to the solution which was refluxed under argon at 110° C. during 50 min until about 1 ml of water separated. The solvent was removed in a rotary evaporator (45° C./250-10 mbar) to obtain 12.11 g of white-beige crystals of racemic trans-2-(benzylidenamino)-cyclohexanol, m.p. 86° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:13]1[N:12]=[C:11]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OCc1cccc(O)c1
Reactant: Cc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cccc(Oc2cccc(CO)c2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
3-Hydroxymethyl-phenol (3.69 g, 29.7 mmol), 2-fluoro-6-methyl-pyridine (3.00 g, 27 mmol,) and cesium carbonate (9.68 g, 29.7 mmol) were suspended in dimethylsulfoxide (25 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (250 mL) and ethyl acetate (250 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-50%, EtOAc:heptane) to afford the title compound (3.72 g, 64% yield) as an off-white solid.
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[C:12]([CH3:26])[CH:13]=[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[CH3:25])[C:9]2=[N:8][C:7]=1[CH3:27])(OCC)=[O:2].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH3:27][C:7]1[N:8]=[C:9]2[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[CH3:25])=[CH:13][C:12]([CH3:26])=[CH:11][N:10]2[C:6]=1[CH2:1][OH:2]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3C)cc(C)cn12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)c(CO)n2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.4 g (1.1 mmol) of 3-carboethoxy-2,6-dimethyl-8-(2,6-dimethyl-4-fluorobenzylamino)-imidazo[1,2-a]pyridine in 10 ml toluene was chilled with ice-water, (2.1 g, 6.6 mmol). Red-l 65% in toluene was added after 30 min. The solution was stirred for 2 h at room temperature. 10 ml of Rochelle-salt solution, (35 g sodium potassium tartrate tetrahydrate/250 ml water) was added dropwise, 10 ml toluene was added, the organic layer was separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure.