Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:31])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (74 mg, 0.237 mmol), 5-fluoro-1,3-dihydro-indol-2-one (40 mg, 0.267 mmol, commercially available from Aldrich) in 0.66 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with anhydrous ethanol (1 ml×3), purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 54.8%) as a yellow solid
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[F:34][C:35]([F:44])([F:43])[C:36](N1C=CN=C1)=[O:37]>C1COCC1>[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH2:30][C:36](=[O:37])[C:35]([F:44])([F:43])[F:34])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: CCc1cc(C(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C(n1ccnc1)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C(=O)CC(=O)C(F)(F)F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (1.79 g, 11.1 mmol) in THF (37 ml) was added n-butyl lithium (1.52 M solution in hexane; 7.3 ml, 11.1 mmol) dropwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes, then cooled at −78° C. A solution of 1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-1-ethanone (2.57 g, 9.23 mmol) in THF (40 ml) was added dropwise, and the mixture was stirred at −78° C. for 1 hour. 1-(Trifluoroacetyl)imidazole (2.0 g, 12.2 mmol) was added, and the mixture was stirred at −78° C. for 3 hours, and quenched with water. The reaction mixture was warmed up to room temperature, and diluted with ethyl acetate. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without further purification. (3.45 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[N:35]1[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:41]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[O:42])[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)c1ccncc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 3.0 ml (21.6 mmol) of triethylamine in 15 ml of CH2Cl2 cooled to 0° C. was added 1.7 g (9.5 mmol) ml of 4-pyridinecarbonyl chloride (isonicotinoyl chloride). The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was washed with H2O, 2 N citric acid, and brine and then dried with Na2SO4. The solvent was removed to give 1.8 g of a light tan solid; Anal. for C24H23N3O6S: Calc'd: C,59.9; H,4.8; N,8.7; S,6.6; Found: C,59.0; H,4.8; N,8.5; S,6.9; Mass spectrum (ES) 482.6(M+H).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:40])=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CSc1ccc(COC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(COC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a mixture of 4-methylsulfanylbenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 345 (300 mg, 0.67 mmol) and methylene chloride (10 ml), m-chloroperbenzoic acid (210 mg, 0.85 mmol) was added followed by stirring for 2 hours with cooling on ice-bath. The reaction mixture was washed with a saturated sodium sulfite solution, a saturated sodium hydrogencarbonate solution, and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from isopropyl alcohol-ether to afford 4-methanesulfinylbenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (203 mg, yield 65%) as a white powder.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[CH:35]1[CH2:37][CH2:36]1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH:35]3[CH2:37][CH2:36]3)[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc(Cl)c1C1CC1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C4CC4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-cyclopropyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=487, obsd=487). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.46 (d, J=5.2 Hz, 1H), 6.17 (s, 2H), 4.19 (d, J=12.9 Hz, 2H), 3.92 (t, J=6.1 Hz, 2H), 3.12 (t, J=6.7 Hz, 4H), 3.05-2.88 (m, 4H), 2.72 (t, J=6.1 Hz, 2H), 1.98-1.82 (m, 6H), 1.50 (p, J=6.7 Hz, 1H), 1.25 (dd, J=6.9, 1.3 Hz, 6H), 1.02 (d, J=8.1 Hz, 2H), 0.43 (d, J=5.2 Hz, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1O>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Reactant: Oc1ccc(F)cc1F
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(F)cc2F)CC1
Yield: 21 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and 2,4-difluorophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 21%). MS (m/e): 454.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=O)[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].Cl.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH2:35])[CH2:32]2.C(SC1N(C2C=CC(C(OC)=O)=CC=2)N=CC=1C(N1CCC(C2C=CC=CC=2C(F)(F)F)C1)=O)CC>>[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH:35][C:21]([C:15]1[CH:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:11][CH:10]=3)[C:16]=1[S:17][CH2:18][CH2:19][CH3:20])=[O:23])[CH2:32]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Agent: CCCSc1c(C(=O)N2CCC(c3ccccc3C(F)(F)F)C2)cnn1-c1ccc(C(=O)OC)cc1
Agent: Cl
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(CC(=O)OC)cc1

Procedure:
Prepared from 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #35) and 2-adamantylamine hydrochloride by the same procedure as used for Intermediate #6.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@H:3]([CH3:31])[CH2:2][NH:1][C:34](=[O:35])[C@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@H]1O
Product: C[C@H](CNC(=O)[C@H](O)CCO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 54 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 54% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 1.43-1.57 (m, 3H), 1.71-1.86 (m, 1H), 3.33-3.53 (m, 3H), 3.65-3.79 (m, 1H), 3.88-4.00 (m, 1H), 4.36 (t, 1H), 4.85-4.96 (m, 1H), 5.29 (s, 2H), 5.45 (d, 1H), 7.24 (d, 2H), 7.28-7.41 (m, 2H), 7.59 (t, 2H), 7.71 (t, 1H), 7.87 (t, 1H), 8.10-8.21 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.99 (s, 1H); Mass spectrum MH+ 537.9.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:13][NH:14][CH3:15]>CS(C)=O>[CH:10]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:14]([CH3:15])[CH3:13])=[CH:3][CH:4]=2)=[O:9])[CH2:12][CH2:11]1
Reactant: CNC
Reactant: O=C(c1ccc(F)cc1)C1CC1
Solvent: CS(C)=O
Product: CN(C)c1ccc(C(=O)C2CC2)cc1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
Cyclopropyl p-fluorophenyl ketone (1.12 g, 6.9 mmol) is added to 3 ml of dimethylsulfoxide (DMSO). The flask is sealed with a septum and the solution stirred and cooled to 0° C. in an ice bath. Anhydrous dimethylamine (3.4 g, 75.5 mmol) is added by syringe and the solution is gradually warmed to room temperature and allowed to stir at room temperature for 72 hrs. The precipitate is filtered and washed with DMSO and ether. Recrystallization from acetone-pentane (1:1) yielded p-N,N-dimethylaminophenyl cyclopropyl ketone as a white crystalline solid (1.22 g, 92.8%); m.p. 139°-141° C.; IR (KBr):158 cm-1 (C=O); NMR (CDCl3) δ:0.99 (m,2H); 1.16 (m,2H ) 2.60 (m,1H); 3.05 (s,6H); 6.67 (d,2H); 7.96 (d,2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1[CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.O1CCCC1.Cl>C(O)C>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: O=CNc1nc(CSc2ccncc2)c(Cl)s1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1nc(CSc2ccncc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.9 %

Procedure:
A solution of 5-chloro-2-formylamino-4-(4-pyridylthiomethyl)thiazole (4.9 g) in a mixture of ethanol (25 ml), tetrahydrofuran (20 ml) and concentrated hydrochloric acid (7 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8 using aqueous sodium bicarbonate under ice-cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-chloro-4-(4-pyridylthiomethyl)thiazole (0.26 g, yield: 56.6%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C([Li])CCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].O>C1COCC1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(Br)cs1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc(C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.8 %

Procedure:
To a solution of 4-bromo-2-methylthiazole (950 mg, 5.3 mmol) in absolute THF (40 mL) at −78° C. was added dropwise n-butyllithium (2.7 mL, 1.6 M in hexane). The solution was stirred at −78° C. for 1 h, then tributyltinchloride (2.2 g, 6.8 mmol) was added, and the mixture was allowed to warm to room temperature. Water (90 mL) was poured into the reaction mixture and the phases were separated. The aqueous layer was extracted with diethyl ether (4×30 mL). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The resulting oil was purified by fractionated Kugelrohr distillation to give the title compound (2.3 g). The product was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[Br:19]([O-])(=O)=O.[K+]>>[Br:19][C:10]1[CH:9]=[C:8]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc(CC(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
4′-isobutylacetophenone (215 g) was added to 49% sulfuric acid (1 Liter) was and potassium bromate (268 g) was added under ice-cooling over 1.5 h. The mixture was warmed to room temperature and stirred further for 1 h, which was followed by extraction with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The remaining oily substance was distilled under highly reduced pressure to give 3′-bromo-4′-isobutylacetophenone (182 g), boiling point: 130–140° C./0.15 mmHg
Reaction SMILES: FC1C([O:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=2)=C(F)C(F)=C(F)C=1F.[CH3:24][C:25]1[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[C:44]([CH3:50])[C:26]=1[CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:39]=[CH:38][O:37][C:36]=2[C:40]([NH:42][NH2:43])=[O:41])[CH:32]=[CH:33][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:17]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[OH:16])[C:9]([NH:43][NH:42][C:40]([C:36]1[O:37][CH:38]=[CH:39][C:35]=1[C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:27][C:26]2[C:44]([CH3:50])=[C:45]([CH3:49])[CH:46]=[C:47]([CH3:48])[C:25]=2[CH3:24])[CH:30]=1)=[O:41])=[O:8])#[N:18]
Reactant: N#Cc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1O
Reactant: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NN)c2)c1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NNC(=O)c3ccc(O)c(C#N)c3)c2)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A mixture of 3-cyano-4-hydroxybenzoic acid pentafluorophenyl ester (compound of Reference Example 63; 0.45 g) and 3-[3-(2,3,5,6-tetramethylbenzyloxy)phenyl]-2-furancarboxylic acid hydrazide (compound of Reference Example 4; 0.50 g) in DMF (5 ml) was stirred at 70° C. overnight. The reaction solution was then diluted with ethyl acetate, washed with 1 M hydrochloric acid and water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0%→10% methanol/chloroform gradient) and recrystallized from ethyl acetate, thereby giving 0.31 g of the desired compound. Melting point: 210-211° C.
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][C@@H:9]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C@@H:8]([NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:38](C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:1]([N:4]([CH3:38])[C@H:5]1[CH2:10][C@@H:9]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C@@H:8]([NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:7][CH2:6]1)([CH3:2])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)N[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](C(=O)OC(C)C)C1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)OC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A solution of (1R,2S,5R)-isopropyl 5-(isopropylamino)-2-(2-(3-trifluoromethyl-benzamido)acetamido)cyclohexanecarboxylate (210 mg, 0.45 mmol; Example 11l) in 10 ml of CH2Cl2 is treated with 37% aqueous formaldehyde (0.5 ml) and NaBH(OAc)3 (0.3 g, 1.4 mmol) powder and stirred at room temperature for 2 hours. The mixture was treated with 1 N NaOH and stirred at room temperature for 1 hr and extracted into CH2Cl2. The extract was washed with water, brine, dried over Na2SO4, filtered and the solvent evaporated to give 200 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.16 (s, 1 H), 8.06 (d, J=7.8 Hz, 1 H), 7.86 (bt, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.55 (t, J=7.8 Hz, 1 H), 7.21 (bs, 1 H), 4.91 (m, 1 H), 4.51 (m, 1 H), 4.12 (d, J=5.2 Hz, 2 H), 3.01 (m, 1 H), 2.58 (m, 1 H), 2.57 (m, 2 H), 2.21 (s, 3 H), 2.02-1.40 (m, 7 H), 1.16 (m, 6 H), 1.02 (m, 6 H). MS found: (M+H)+=486.46.
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][C:7]3([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8][CH:9]([CH2:11][C:5](O)([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[BrH:20]>C(O)(=O)C.O>[Br:20][C:5]12[CH2:6][C:7]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:8][CH:9]([CH2:10][C:3]([CH2:1][CH3:2])([CH2:12]3)[CH2:4]1)[CH2:11]2
Reactant: Br
Reactant: CCC12CC3CC(O)(C1)CC(c1ccccc1)(C3)C2
Solvent: CC(=O)O
Solvent: O
Product: CCC12CC3CC(Br)(C1)CC(c1ccccc1)(C3)C2
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Stir 0.03 mol of 1-ethyl-3-hydroxy-5-phenyl adamantane (III) with 100 ml of 40% HBr in glacial acetic acid for 20 min at 60° C. and for 30 min at room temperature. Subsequently dilute the reaction mixture with water and extract with ether. Wash the combined organic extracts with sodium chloride solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 68%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[N:17]=[C:18]=[S:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][C:6](=[O:8])[N:17]([C:11]2[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])[C:18]1=[S:19])[CH:2]=[CH2:3]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: C=CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Yield: 16.3 %

Procedure:
A mixture of N-allyl glycine (17.4 g), 2,6-dimethylphenyl-isothiocyanate (20 g), triethylamine (20.2 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was evaporated to dryness. The residual gum was dissolved in diethyl ether, then treated with etheral hydrogen chloride. A white solid formed. The solid was filtered and discarded. The filtrate was concentrated to a residue. The residue was chromatographed on silica gel (CH2Cl2) to give title compound (5.2 g) as an orange solid, m.p. 43°-46° C. Anal. Calcd. for. C14H16N2O S: C, 64.59; H, 6.19; N, 10.76. Found: (2, 64.52; H, 6.08; N, 10.66. Mass spectrum (EI, M.+) m/z 260.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Nc2nccs2)cc1
Reactant: ClCCN1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(N(CCN2CCCC2)c2nccs2)cc1

Procedure:
A solution of 1.0 g (5.2 mmol) of N-(4-fluorophenyl)thiazol-2-amine in 25 mL of THF was treated with 10.3 mL (10.3 mmol) of a 1.0 M solution of NaHMDS in THF and 0.88 g (5.2 mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride and heated at reflux for 18 h. The reaction mixture was poured into 250 mL of EtOAc and extracted thrice with 1 M aqueous HCl. The combined acidic extracts were brought to pH 12 with a 10% (w/v) solution of Na2CO3 and extracted five times with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography eluting with a linear gradient of neat EtOAc to 20% MeOH in EtOAc to deliver the desired compound. MS (M+H)+ 292.
Reaction SMILES: CC1C=CC(S(O[CH:12]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[CH3:13])(=O)=O)=CC=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C>C1COCC1>[N+:24]([C:16]1[CH:15]=[C:14]([CH:12]([N:37]2[CH2:36][CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:39][CH2:38]2)[CH3:13])[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1)([O-:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC(C)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.1 %

Procedure:
Stir the mixture of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl 4-methylbenzenesulfonate (350 mg, 0.90 mmol), 1-piperazinecarboxylic acid tert-butyl ester (335 mg, 1.8 mmol) and diisopropylethylamine (232 mg, 1.8 mmol) in THF (10 mL) for 12 hrs at 80° C. Concentrate the reaction mixture to obtain the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:10) to afford the title compound (280 mg, 77.1%). MS: (M+1): 404.2.