Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]([OH:22])[CH2:19][NH:20][CH3:21])[CH:15]=[CH:16][CH:17]=1.[Cl:23][C:24]1[CH:46]=[CH:45][C:27]([CH2:28][NH:29][C:30]([C:32]2[C:33](=[O:44])[C:34]3[CH:41]=[C:40]([CH2:42]Cl)[O:39][C:35]=3[N:36]([CH3:38])[CH:37]=2)=[O:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[Cl:23][C:24]1[CH:46]=[CH:45][C:27]([CH2:28][NH:29][C:30]([C:32]2[C:33](=[O:44])[C:34]3[CH:41]=[C:40]([CH2:42][N:20]([CH2:19][CH:18]([OH:22])[C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=4)[CH3:21])[O:39][C:35]=3[N:36]([CH3:38])[CH:37]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: CNCC(O)c1cccc(OC)c1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc(C(O)CN(C)Cc2cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3o2)c1
Temperature: 90 °C
Yield: 48.7 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL) and 1-(3-methoxyphenyl)-2-(methylamino)ethanol (Preparation 31, 0.112 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into water (25 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.102 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 116-120° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.54, 7.41-7.32, 7.18, 6.88-6.85, 6.77-6.75, 5.10, 4.704.66, 4.55, 3.89, 3.74, 3.70, 2.61, 2.33; MS (ESI+) m/z 510 (M+H)+. Anal. Found: C, 63.48; H, 5.56; N, 8.24; Cl, 6.94.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1C(O)=O)([O-:3])=[O:2].[CH:16]([C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:20]=1[NH2:21])([CH3:18])[CH3:17].[C:29](OCC)(=[O:31])C>>[CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:19]([CH:16]([CH3:18])[CH3:17])[C:20]=1[N:21]1[C:7](=[O:9])[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[C:10]2[C:29]1=[O:31])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 45 %

Procedure:
0.386 g of anhydride obtained by dehydrating 3-nitrophthalic acid at a temperature of about 220° C., and 0.354 g of 2,6-diisopropylaniline were mixed, and reacted at a temperature of 180° C. for 4 hours. After the reaction was finished, the reaction mixture was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and subjected to filtration. The filtrate was concentrated and dried and solidified. Then, it was recrystallized by using a mixture of hexane and ethyl acetate, to obtain 0.320 g (yield 45%) of the specified compound.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:48][C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][N:57]([C:60](=[O:70])[CH2:61][C:62]3[CH:67]=[C:66]([CH3:68])[CH:65]=[CH:64][C:63]=3[CH3:69])[CH2:56][CH2:55]2)[S:52][CH:53]=1>C(#N)C>[CH3:69][C:63]1[CH:64]=[CH:65][C:66]([CH3:68])=[CH:67][C:62]=1[CH2:61][C:60]([N:57]1[CH2:56][CH2:55][CH:54]([C:51]2[S:52][CH:53]=[C:49]([NH:48][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:11])[N:50]=2)[CH2:59][CH2:58]1)=[O:70]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(N)cs3)CC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(NC(=O)C(C)c4ccccc4)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a solution of (rac.)-2-phenylpropionic acid (46 mg, 0.30 mmol) and diisopropylethylamine (0.15 mL, 0.9 mmol) in acetonitrile (2 mL) is added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (322 mg, 0.73 mmol) at RT. After stirring 30 min at RT, 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(2,5-dimethyl-phenyl)-ethanone (100 mg, 0.30 mmol) is added to the reaction mixture. After stirring overnight at RT, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (ethylacetate/cyclohexane 1:1) to give N-(2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-2-phenyl-propionamide (Compound No. I.g.141, 19 mg, 13.4%). 1H-NMR (400 MHz, CDCl3): δ=1.46-1.39 (m, 1H), 1.52 (d, 3H), 1.68-1.56 (m, 1H), 1.89-1.83 (m, 1H), 2.01-1.97 (m, 1H), 2.15 (s, 3H), 2.19 (s, 3H), 2.73-2.67 (m, 1H), 3.18-2.92 (m, 2H), 3.59 (s, 2H), 3.68-3.63 (q, 1H), 3.78-3.71 (m, 1H), 4.65-4.62 (m, 1H), 6.91-6.82 (m, 2H), 7.02-6.98 (m, 1H), 7.31-7.15 (m, 5H), 7.42 (s, 1H), 8.05 (br, 1H). MS: m/z=462 (M+1).
Reaction SMILES: C1CC[CH:4]([N:7]=C=NC2CCCCC2)CC1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([F:40])([C:37]([OH:39])=O)[CH:32]([F:36])[CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].FC1C(F)=CC=CC=1C1C=CC(OCCCCCCC)=CC=1.CN(CCN(C)C)C.[C:71](=[O:73])=[O:72]>C(Cl)Cl.C1COCC1.CCCCCC>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:71]([OH:73])=[O:72])=[C:32]([F:36])[C:31]=2[F:40])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:4]([C:31]([CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][OH:39])#[N:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCOc1ccc(C2=CC=CC(F)C2(F)C(=O)O)cc1
Reactant: O=C=O
Agent: CCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: CN(C)CCN(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCC(C)(C#N)CO
Product: CCCCCCCOc1ccc(-c2ccc(C(=O)O)c(F)c2F)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
0.1 mol of DCC, dissolved in methylene chloride, is added to a mixture of 0.1 mol of 4'-heptyloxy-2,3-difluorobiphenylcarboxylic acid (preparation: 0.1 mol of 2,3-difluoro-4'-heptyloxybiphenyl and 0.1 mol of TMEDA are dissolved in 200 ml of THF and the solution is cooled to -78° C. and reacted with 0.105 mol of a 1.6 N solution of Buli in hexane at this temperature. The reaction mixture is stirred at -78° C. for 3 hours and is then poured all at once onto 200 g of crushed dry ice. Customary working up gives 4'-heptyloxy-2,3-difluoro-biphenyl-4-carboxylic acid), 0.1 mol of optically active 2-cyano-2-methylhexan-1-ol (which can be prepared from optically active ethyl 2-methyl-2-butylcyanoacetate by reduction with LiBH4) and a catalytic amount of 4-N,N'-dimethylaminopyridine (DMAP) in 200 ml of methylene chloride at 0° C. The mixture is then stirred at room temperature for 12 hours. It is worked up in the customary manner and the product is purified by crystallization. Optically active 2-cyano-2-methylhexyl 4'-heptyloxy-2,3-difluorobiphenyl-4-carboxylate is obtained.
Reaction SMILES: BrC1C=CC(O)=CC=1N(CC)CC1C=CC(OCCN2CCCCC2)=C(F)C=1.[C:29]([N:32]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)=[C:47]([F:60])[CH:46]=1)[C:33]1[CH:34]=[C:35]([O:40][C:41](=[O:43])[CH3:42])[CH:36]=[CH:37][C:38]=1[Br:39])(=O)[CH3:30].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Br:39][C:38]1[CH:37]=[CH:36][C:35]([O:40][C:41](=[O:43])[CH3:42])=[CH:34][C:33]=1[N:32]([CH2:29][CH3:30])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]2)=[C:47]([F:60])[CH:46]=1
Reactant: CC(=O)Oc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Agent: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To the total amount of 4-bromo-3-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}phenol crude product, which was synthesized from acetic acid 3-{acetyl-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-4-bromophenyl ester (300 mg) synthesized according to an analogous synthetic method to Example 337 described below, were added pyridine (3 ml) and acetic anhydride (3 ml), and the solution was stirred overnight at room temperature. To reaction mixture was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-methanol system) to provide the title compound (200 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5](=[O:6])[C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: O=C(CCCCl)c1cccnc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)c2cccnc2)C[C@H]1OC
Temperature: 70 °C
Yield: 20 %

Procedure:
A mixture of 3.47 parts of 4-chloro-1-(3-pyridinyl)-1-butanone, 4.5 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 1.94 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 67.5 parts of N,N-dimethylformamide was stirred and heated for 48 hours at 70° C. The reaction mixture was evaporated. The residue was washed with a sodium carbonate solution in water and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.36 parts (20%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(3-pyridinyl)butyl]-4-piperidinyl]benzamide; mp. 166.2° C. (compound 1).
Reaction SMILES: [SH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl.Cl[CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[CH:19]=[N:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:21]([N:20]1[CH:19]=[N:18][N:17]=[C:16]1[CH2:15][S:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12])[CH2:22][CH3:23]
Reactant: Nc1ccc(S)c(C(F)(F)F)c1
Reactant: CCCn1cnnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cnnc1CSc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
4-mercapto-3-trifluoromethylaniline (1.0 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (1.1 g) and potassium carbonate (1.4 g) were added to N,N-dimethylformamide (35 ml), and the mixture was stirred overnight at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was evaporated. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate) to give 4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]-3-trifluoromethylaniline (1.4 g) as pale brown oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])=[O:11].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[CH:10]1[CH2:9][CH2:8][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[O:11]1
Reactant: Cc1ccc(C(=O)C=Cc2ccccc2O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C2CCc3ccccc3O2)c(C)c1
Reaction time: 0.5 h

Procedure:
2-Hydroxy-2',4'-dimethylchalcone (8.20 g) was suspended in ethanol (150 ml) and sodium borohydride (2.50 g) was added in portions. The mixture was stirred for 30 min and the resulting solution allowed to stand overnight. The solvent was distilled off and the residue dissolved in chloroform and washed with water. Evaporation of the chloroform gave the crude intermediate carbinol which was boiled under reflux with acetic acid (100 ml) for 2 hr. Evaporation gave an oily residue which was chromatographed on alumina, eluting with toluene. The main fraction, on evaporation of the solvent, was distilled under vacuum to give 2',4'-dimethylflavan, 4.80 g, b.p. 135°-145°/0.8 mm. Hg=107 Pa.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][N:46]=1>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:49]([C:48]2[CH:47]=[N:46][C:45]([Cl:44])=[CH:53][CH:52]=2)=[O:50])([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.527 g, 2.34 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (12 mL) and N-ethyl diisopropylamine (0.48 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.138 g, 2.58 mmol, 1.1 equiv; BOP reagent) 6-chloro-nicotinic acid (0.369 g, 2.34 mmol, 1.0 equiv) and the reaction mixture stirred at rt for 12 h. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.63 g (74%) of the title compound as off-white solid. MS (ISP): 365.1 [M+H]+
Reaction SMILES: N1([O:10][C:11]2[C:12]3[O:19][CH:18]=[C:17]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)C2C=CC=CC=2N=N1.[CH3:33][S:34]([C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([O:10][C:11]2[C:12]3[O:19][CH:18]=[C:17]([CH:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]4)[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2coc3c(On4nnc5ccccc54)ncnc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2coc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc23)CC1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Under an argon atmosphere, the tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate (10 mg, 0.023 mmol) obtained in Step 7 of Example 1 and 4-(methylsulfonyl)phenol (4 mg, 0.023 mmol) were dissolved in anhydrous N,N-dimethyl formaldehyde (0.5 mL), potassium carbonate (5 mg, 0.035 mmol) was added, stirring was conducted at room temperature for 2 hours, water was added, followed by extraction with toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (hexane:ethyl acetate=1:2) to give the titled compound (10 mg, 89%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:39].[Na+]>CO.CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22](=[O:39])[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCSCC3)c2=O)cc1OC
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCS(=O)CC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.7 %

Procedure:
A mixture of 0.9 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-thiopyran-4-yl)quinazoline-2,4(1H,3H)-dione and 0.445 g of sodium periodate in 20 ml of an MeOH/EtOH/water mixture (5/5/1, v/v/v) is stirred overnight at room temperature. The resulting mixture is evaporated under reduced pressure. Water is added and the resulting mixture is extracted with DCM. The organic phase is dried over Na2SO4. The resulting mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0, v/v) to (95/5, v/v) to give 0.99 g of the expected product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].[F:19][C:20]([F:28])([F:27])[C:21]([F:26])([F:25])[C:22](O)=[O:23].C(N(CC)CC)C>C(#N)C>[F:25][C:21]([F:26])([C:20]([F:28])([F:27])[F:19])[C:22]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1)=[O:23]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: NCCCCN
Reactant: ClCc1cccc2nccn12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCCNCc1cccc2nccn12)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
A suspension of 15.13 g (69.69 mmol) of 5-chloromethylimidazo[1,2-a]pyridine-hydrochloride and 12.29 g (139.38 mmol) of 1,4-diaminobutane in 150 ml of acetonitrile was heated for one hour under reflux while stirring. The reaction mixture was cooled to room temperature. The resulting precipitates of 1,4-diaminobutane-dihydrochloride were filtered off. To the filtrate were added 20.61 ml (139.38 mmol) of ethyl ester of pentafluoropropionic acid and 19.43 ml (139.38 mmol) of triethylamine. The mixture was stirred for one hour at room temperature. The solvent was then distilled off under reduced pressure, and the residue was extracted with 200 ml of dichloromethane. The organic layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 13.61 g of the desired compound (53.6%, a pale yellow liquid).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C@H:16]([O:34][P:35]([O:39][CH3:40])([O:37][CH3:38])=[O:36])[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:5]=1.C1COCC1.O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C@H:16]([O:34][P:35]([O:37][CH3:38])([O:39][CH3:40])=[O:36])[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OC)OC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COP(=O)(OC)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 35 °C
Yield: 56.6 %

Procedure:
A mixture of lithium hydroxide (107 mg, 4.48 mmol), (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(dimethoxyphosphoryloxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 121, 500 mg, 0.9 mmol), THF (10 ml), water (2.5 ml), and MeOH (2.5 ml) was heated at 35° C. overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (10 ml) and acidified with an aqueous solution of 6 N HCl, resulting in a precipitate. The solid was collected by filtration to give the title compound (270 mg, yield: 57%). The title compound was used in the preparation of EXAMPLE 30 without further purification.
Reaction SMILES: [CH2:1](O)[C:2]#C.[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])#[N:6]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO>[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:1]#[CH:2])=[O:12])#[N:6]
Reactant: C#CCO
Reactant: COC(=O)CCCCC#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: C#CCOC(=O)CCCCC#N
Yield: 79.3 %

Procedure:
15.1 g (269 mmol) of propargyl alcohol and 1.92 g (7 mmol) of titanium tetraisopropoxide were added to 18.0 g of the obtained methyl 5-cyanovalerate, and heated and stirred at 120° C. for 8 hours while methanol was removed. After the reaction, methanol and excessive propargyl alcohol were evaporated away under reduced pressure, and the residue was purified through column chromatography (Wakogel C-200, elution with hexane/ethyl acetate=1/9) to give 16.7 g (yield 75%) of 2-propynyl 5-cyanovalerate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:25])=[CH:9]\[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:4][CH:3]=1.FC1C=CC(C(=C)CN2C3C=CC(C)=CC=3C3CN(C)CCC2=3)=CC=1>CO.C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:6][CH:7]=1
Reactant: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: [Pd]
Agent: C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccc(F)cc2)CCN(C)C1

Procedure:
A mixture of compound 5-((Z)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and 5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (of ratio 1:3, 1.8 g, 5.38 mmol, 1 equiv) were shaken in a 250 ml Parr Shaker vessel with 180 mg of Pd/C in 50 ml of Methanol/acetic acid (10:1) mixture for 18 hours under 60 psi H2. It was filtered over a celite bed with methanol and evaporated under vacuum. The residue was diluted with ethyl acetate (500 ml) and washed with 50 ml of satd. sodium bicarbonate solution and then brine. The organic part was concentrated under reduced pressure and column purified over 100-200 silica gel using 0 to 50% ethyl acetate in hexanes as eluant, at an interval of 5%. Yield: 685 mg (38%).