Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([Mg]Cl)[CH2:26][CH3:27].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21]([CH2:25][CH2:26][CH3:27])([OH:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Reactant: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC1(O)CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone were dissolved at room temperature in 5 ml of tetrahydrofuran. A 2M solution of propylmagnesium chloride in diethyl ether (0.31 ml, 2 eq) was added, and stirring at room temperature was continued for 4 h. The reaction was stopped by careful addition of saturated aqueous ammonium chloride solution. The aqueous layer was extracted with methyl tert-butyl ether. The organic layer was dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was chromatographed over silica gel using heptane/ethyl acetate 20:1 as the eluent. 54 mg of the title compound were isolated as a pale yellow oil (48%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10]/[N:11]=[C:12](\[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])/[C:13]([O:15][CH3:16])=[O:14]>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10]/[N:11]=[C:12](\[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:24][Br:1])/[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CO/N=C(/C(=O)OC)c1c(C)cccc1CBr
Yield: 10.6 %

Procedure:
A mixture of N-bromosuccinimide (11 g, 0.596 mol), 2,2-azobisisobutyronitrile (89 mg, 0.540 mol) and methyl E-2,6-dimethylphenylglyoxylate O-methyl oxime (12 g, 0.542 mol) in CCl4 (200 mL) was refluxed for 4 hours under 300 W lamp. The cooled reaction mixture was filtered, concentrated in vacuo to give the product (17.2 g, 100%) which was used in the next reaction without further purification:
Reaction SMILES: C(O)(C(F)(F)F)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCOC3C=CC(C4C(C#N)=CSC=4)=CC=3)=C(C(O)=O)N=1)CC2)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCI)=C(C(OCC)=O)N=1)CC2)=O.[S:91]1[C:95]2[CH:96]=[CH:97][CH:98]=[CH:99][C:94]=2[N:93]=[C:92]1[NH:100][C:101]([C:103]1[CH:104]=[CH:105][CH:106]=[C:107]2[C:112]=1[CH2:111][N:110]([C:113]1[N:118]=[C:117]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[C:116]([CH2:126][CH2:127][CH2:128]I)=[CH:115][CH:114]=1)[CH2:109][CH2:108]2)=[O:102].[Cl:130][C:131]1[CH:136]=[C:135]([OH:137])[CH:134]=[CH:133][N:132]=1>>[S:91]1[C:95]2[CH:96]=[CH:97][CH:98]=[CH:99][C:94]=2[N:93]=[C:92]1[NH:100][C:101]([C:103]1[CH:104]=[CH:105][CH:106]=[C:107]2[C:112]=1[CH2:111][N:110]([C:113]1[N:118]=[C:117]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[C:116]([CH2:126][CH2:127][CH2:128][O:137][C:135]3[CH:134]=[CH:133][N:132]=[C:131]([Cl:130])[CH:136]=3)=[CH:115][CH:114]=1)[CH2:109][CH2:108]2)=[O:102]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCI
Reactant: Oc1ccnc(Cl)c1
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Agent: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCOc1ccnc(Cl)c1

Procedure:
Compound 109A was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A and compound 2C with compound 96D and 2-chloropyridin-4-ol, respectively: APCI (+)/LC/MS: 657 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]([O:25]CC)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1.O.Cl>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]([OH:25])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccccc1)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)n1ncc(-c2nc(C(Cc3ccccc3)C(=O)O)cs2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a mixed solution of the compound (14 mg, 0.03 mmol) obtained in step 1 in ethanol (1.0 mL) and THF (1.0 mL) was added 1N aqueous sodium hydroxide solution (0.059 mL, 0.06 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water, 1N hydrochloric acid was added until the mixture became pH 2-3, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure to give 2-(2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)-3-phenylpropanoic acid (11.4 mg, 0.025 mmol, 87%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH3:9][O:10][CH:11]([O:15][CH3:16])[CH2:12][C:13]#[N:14].C[O-].[Na+]>CO>[OH2:8].[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:13]#[N:14]
Reactant: COC(CC#N)OC
Reactant: O=Cc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C#N)=Cc1cccnc1
Product: O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Pyridine-3-carboxaldehyde (80.25 g, 0.75 mol) and 3,3-dimethoxypropionitrile (115.1 g, 1.0 mol) were mixed together and added to a solution of sodium methoxide (54.0 g, 1.0 mol) in methanol (400 mL) over a period of 15 minutes. The mixture was stirred at room temperature overnight. Most of the methanol was evaporated in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (450 mL). The organic layer was separated, washed with brine (400 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residual oil was distilled in vacuo to give 80.3 g (52%) of the product as a colorless oil, bp 130-140° C. (2 mm Hg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:18])[CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Cu](Cl)Cl.C(O)C>[C:19]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[C:2]=2[O:1][C:10]([CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:9][C:8]3=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CC(=O)C1CCOCC1)c1cccc(-c2ccccc2)c1O
Agent: Cl[Cu]Cl
Solvent: CCO
Product: O=c1cc(C2CCOCC2)oc2c(-c3ccccc3)cccc12
Temperature: 140 °C

Procedure:
A 5 mL microwave vial was charged with a magnetic stirring bar, crude 1-(2-hydroxybiphenyl-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione (320 mg, 1 mmol), ethanol (3 mL), and copper (II) chloride (13 mg, 0.1 mmol). The reaction vial was sealed, the reaction mixture magnetically stirred and heated via microwave irradiation to 140° C. for 10 minutes. The resulting solution was concentrated in vacuo and purified by high-pressure liquid chromatography to give 8-phenyl-2-(tetrahydro-2H-pyran-4-yl)-4H-chromen-4-one (67).
Reaction SMILES: ClC1C=NC=C(Cl)C=1N[C:9]([C:11]1[C:20](=O)[C:19]2C(=N[CH:16]=[CH:17][CH:18]=2)N(N2CCN(C)CC2)C=1)=[O:10].[Cl:30][C:31](OC)=[O:32]>>[Cl:30][C:31]([O:10][CH2:9][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:32]
Reactant: CN1CCN(n2cc(C(=O)Nc3c(Cl)cncc3Cl)c(=O)c3cccnc32)CC1
Reactant: COC(=O)Cl
Product: O=C(Cl)OCc1ccccc1

Procedure:
The same reaction was carried out as in Example 23, except for using N-(3,5-dichloropyridin-4-yl)-1-(4-methylpiperazin-1-yl)-1,4-dihydro[1,8]naphtyridin-4-one-3-carboxamide, instead of ethyl 1-(1-benzylpiperidin-3-yl)-1,4-dihydro[1,8]naphtyridin-4-one-3-carboxylate and using methyl chloroformate, instead of benzyl chloroformate, to obtain 85 mg (53%) of the above-identified compound as a colorless crystal.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([SH:13])[CH2:11][CH3:12]>>[CH2:10]([S:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCCS
Product: CCCSc1ccc(C#N)cc1

Procedure:
1 g of 4-fluorobenzonitrile was used in Procedure Q with 1-propanethiol to afford 4-(propylthio)benzonitrile. 860 mg of 4-(propylthio)benzonitrile was reacted via Procedure T to give 4-(propylthio)benzoic acid. 700 mg of 4-(propylthio)benzoic acid was reacted via Procedure R to give 4-(propylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(propylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]3([OH:19])[C:11]4[C:16]([C:17](=[O:18])[C:8]3([OH:20])[C:7]=2[CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH3:2].[C:22]([OH:25])(=O)[CH3:23].N1C=CC=CC=1.C1C[O:35][CH2:34][CH2:33]1>>[C:34]([O:10][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:21][C:7]=1[C:8]1([O:20][C:22](=[O:25])[CH3:23])[C:9](=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]1=[O:18])(=[O:35])[CH3:33]
Reactant: CC(=O)O
Reactant: C1CCOC1
Reactant: CCc1ccc2c(c1)C1(O)C(=O)c3ccccc3C1(O)O2
Solvent: c1ccncc1
Product: CCc1ccc(OC(C)=O)c(C2(OC(C)=O)C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27 %

Procedure:
8-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.80 g, 2.70 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.57 ml, 5.66 mmol), pyridine (0.22 ml, 2.83 mmol), and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.56 g, 27%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:13].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>CS(C)=O.O>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])[CH2:19][CH2:20]1
Reactant: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)NCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
10% sodium hydroxide aqueous solution (7.21 g) was added to a solution containing 3-(2-hydroxyphenyl)-N-(3-morpholinopropyl)propanamide (2.60 g) obtained in Example 5(1) in dimethylsulfoxide (36 ml). The mixture was heated up to 80° C. and 1-bromooctadecane (2.97 g) was added thereto. After being stirred for 2.5 hours at 80° C., the reaction mixture, with water added thereto, was neutralized with 1N hydrochloric acid. The deposited solid was corrected by filtration and washed with water. This solid was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=60:1 to 30:1), thereby yielding the entitled compound (1.99 g) as white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[C:5]1[C:15]([F:18])([F:17])[F:16])[C:2]#[CH:3].[C:19](Br)#[CH:20].[Mg].[Mg].P(O)(O)([O-])=O.[Na+].C(OC(C)C)(C)C>O1CCCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]([OH:14])[C:19]#[CH:20])=[C:5]1[C:15]([F:18])([F:16])[F:17])[C:2]#[CH:3]
Reactant: C#CCn1c(C(F)(F)F)c(C=O)c2ccccc21
Reactant: C#CBr
Agent: O=P([O-])(O)O
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: C#CCn1c(C(F)(F)F)c(C(O)C#C)c2ccccc21
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4.5 g of 1-(2-propynyl)-2-trifluoromethyl-3-formyl-(1H)-indole in 30 ml of tetrahydrofuran were cooled at -15° C. and over 15 minutes, 26 ml of a solution of magnesium ethynyl bromide in tetrahydrofuran (0.8M ) were added. After stirring for one hour at -5° C., another 5 ml of magnesium solution were added, and the mixture was allowed to return to ambient temperature. After stirring for 30 minutes and then pouring into a saturated aqueous solution of monosodium phosphate, extraction was carried out with isopropyl ether. The solvent was eliminated under reduced pressure to obtain 5.89 g of crude product which was purified by chromatography over silica (eluent: hexane-ethyl acetate 9-1) to obtain 1.91 g of 1(RS) [1-(2-propynyl)-2-trifluoromethyl-(1H)-indol-3-yl]-prop-2-ynyl alcohol melting at 98° C.
Reaction SMILES: O1C2C=CC(C3(C(NC4C=CC(C(O)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:41]3([C:44]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([CH:53]([O:62][CH2:63][CH2:64][CH2:65]O)[C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[O:60][CH3:61])=[CH:49][N:48]=4)=[O:45])[CH2:43][CH2:42]3)=[CH:40][C:35]=2[O:34][CH2:33]1>C(O)CC>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:41]3([C:44]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([CH:53]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[O:60][CH3:61])[O:62][CH2:63][CH2:64][CH3:65])=[CH:49][N:48]=4)=[O:45])[CH2:43][CH2:42]3)=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Solvent: CCCO
Product: CCCOC(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(propoxy)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and propan-1-ol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])#[CH:15].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(#N)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:12]=1
Reactant: C#Cc1ccccc1OC
Reactant: O=C(O)COc1ccc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1C#Cc1cc(Cl)ccc1OCC(=O)O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of (2-bromo-4-chlorophenoxy)acetic acid (200 mg; 0.75 mmol, Intermediate 4) and 2-ethynylanisole (Aldrich, 107 μL; 0.83 mmol) in anhydrous, degassed ACN (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol) followed after 5 minutes by copper iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.3 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvents were removed under vacuum, the residue was then taken up in EtOAc and washed with HCl (1N aqueous solution), the organic phase was washed with water (750 mL) then with brine (750 mL), dried over MgSO4, filtered and concentrated under vacuum to give a brown oily residue which was purified by preparative HPLC to afford the title compound as a brown oil.
Reaction SMILES: [C:1]([CH:4]([CH2:8][C:9]#[C:10][CH3:11])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH3:12][O:13]C(OC)(C)C.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:7][C:5]([O:13][CH3:12])([CH:4]([C:1](=[O:3])[CH3:2])[CH2:8][C:9]#[C:10][CH3:11])[CH3:6]
Reactant: COC(C)(C)OC
Reactant: CC#CCC(C(C)=O)C(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC#CCC(C(C)=O)C(C)(OC)OC

Procedure:
A solution of 38.0 g. (0.25 mol.) of 3-acetyl-5-heptyn-2-one, 32.3 g. (0.31 mol.) of 2,2-dimethoxy-propane, and 5 mg. of p-toluenesulfonic acid in 25 ml. of absolute methanol and 25 ml. of benzene was slowly distilled until the material boiling below 65° had been removed, then stirred with 1 g. of sodium carbonate and filtered to produce 2,2-dimethoxy-3-acetyl-5-heptyne in the filtrate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>CCCCCC>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2([OH:37])[C:31]3[C:38]([CH3:39])=[C:27]([N:24]4[CH2:25][CH2:26][N:21]([C:18]5[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=5)[CH2:22][CH2:23]4)[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]=3[O:34][C:33]2([CH3:35])[CH3:36])=[CH:3][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(OC(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Yield: 82 %

Procedure:
Using 1-bromo-4-(trifluoromethoxy)benzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 82%. mp. 175–176° C. (hexane).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].Cl>O1CCOCC1>[ClH:1].[NH2:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]2[N:7]=[C:2]([Cl:1])[C:3]([C:22]#[N:23])=[N:4][CH:5]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ncc(N2CCC[C@@H](N)C2)nc1Cl

Procedure:
(R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87) (1.5 g) was treated with 30 mL “4N HCl in dioxane” at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile hydrochloride (134) in quantitative yield. Compound 134 (1.20 g, 4.4 mmol) and p-anisic acid (1.34 g, 8.8 mmol) were dissolved in 20 mL DMF with DIEA (3.82 mL, 22.0 mmol). To it was added PyBOP (4.58 g, 8.8 mmol). The mixture was stirred at RT for 30 m. It was diluted with EtOAc (200 mL), washed with 1N NaOH and water. The organic phase was dried, concentrated and subjected to flash column with 0 to 50% EtOAc in DCM to isolate (R)—N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-4-methoxybenzamide, compound 135 (yield >90%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:17]I>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:17])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCNc1ccc(CC(=O)OC)cc1
Reaction time: 1 h

Procedure:
A solution of 20.7 g. of 4-(allylamino)phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 4-(allylamino)phenylacetate.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:3]1=[O:14].[OH:15][C@@H:16]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH:36]=1)[CH2:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO>[OH:15][C@@H:16]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH:36]=1)[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:3]2=[O:14])[CH2:20][CH2:19]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCC(=O)CC3)ccc2s1
Reactant: N[C@@H]1CCN(c2ccc(Cl)cc2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCC(N[C@@H]4CCN(c5ccc(Cl)cc5)C4=O)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one as prepared in Example 14 (0.08 g) in EtOH (3 ml) was added 1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one as prepared in Example 13 (0.15 g, 0.53 mmol) and sodium triacetoxyborohydride (0.112 g, 0.53 mmol). The reaction was stirred at room temperature for 48 hours. The solvent was removed and the residue purified using preparative TLC (10:1 DCM:MeOH) to yield (3R)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)-1-(4-chlorophenyl)pyrrolidin-2-one.
Reaction SMILES: [S:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5]2)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([Cl:29])[N:24]=2)[CH2:19][CH2:18]1>C(Cl)Cl>[Cl:29][C:25]1[N:24]=[C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:7](=[O:9])[CH:6]4[S:1][CH:2]([CH2:3][CH2:4][CH2:5]4)[C:10]3=[O:11])[CH2:22][CH2:21]2)[CH:28]=[N:27][CH:26]=1
Reactant: O=C1OC(=O)C2CCCC1S2
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Solvent: ClCCl
Product: O=C1C2CCCC(S2)C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1

Procedure:
Tetrahydrothiopyran-2,6-dicarboxylic anhydride (3.7 g., 21 mmole) and 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine (5.63 g., 21 mmole) were combined in 200 ml. of methylene chloride and stirred for 30 minutes at room temperature. The solvent was removed in vacuum and 200 ml. of toluene added. The mixture was refluxed for 48 hours with water removal via a Dean-Stark trap. Upon cooling, the reaction was concentrated to an oil and this was dissolved in 2% ethanol/chloroform and filtered through silica gel. The fractions which contained the product were concentrated in vacuum and the resulting residue was recrystallized from isopropyl alcohol with the addition of 4N isopropanolic HCl. 0.6 Grams of the title compound was obtained as the hydrochloride, hydrate; m.p. 248°-250° C.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(/[CH:22]=[CH:23]/[CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(C)(C)C)(C)(C)C.[K]>C(COC)OC>[ClH:11].[ClH:11].[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][O:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][N:25]([CH2:24]/[CH:23]=[CH:22]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:26][CH2:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1Oc1ccccc1
Reactant: OCCN1CCN(C/C=C/c2ccccc2)CC1
Agent: CC(C)(C)OC(C)(C)C
Agent: [K]
Solvent: COCCOC
Product: C(=C/c1ccccc1)\CN1CCN(CCOCc2ccccc2Oc2ccccc2)CC1
Product: Cl
Temperature: 40 °C
Reaction time: 72 h

Procedure:
7.82 g (3.58 mmol) of o-phenoxybenzyl chloride dissolved in 8 ml of dimethoxyethane were added dropwise at room temperature to a solution of 8.82 g (35.8 mmol) of (E)-4-(3-phenyl-2-propenyl)-1-piperazineethanol and 4.42 g (39.4 mmol) of potassium tert-butyloxide and 4 g of 3A molecular sieve in 125 ml of dry dimethoxyethane. After stirring for 3 days at 40° C., the mixture was cooled to room temperature. The salts in the solution were filtered off and the solution was evaporated. The residue obtained was purified by means of column chromatography over silica (eluent toluene:ethanol=9:1). The collected fractions were dissolved in ethanol and 5 ml of 4.9 N HCl in ethanol was added. The clearsolution was evaporated. Yield 2.4 g (13%), m.p. 221° C.