Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20](Cl)=[O:21]>[OH-].[Na+]>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1)=[O:21]
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1)C(=O)O
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 0.5 g 2-(4-aminophenoxy)-2-methylpropionic acid in 5 ml 2N NaOH, 0.70 ml 3,5-dichlorobenzoyl chloride was dropwise added with stirring 5 ml additional 2N NaOH was gradually added to keep the PH strongly alkaline during the reaction. After 1 hour stirring, the reaction product was acidified with HCl. The white precipitate was recrystallized from aqueous isopropanol to give 1.4 g (76%) of fine crystals MP 206°-207°.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:6][CH3:7])[O:4][CH3:5].[F:16][C:17]([F:24])([F:23])[S:18]([O:21]C)(=[O:20])=[O:19]>C(OCC)(=O)C>[F:16][C:17]([F:24])([F:23])[S:18]([O-:21])(=[O:20])=[O:19].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[CH3:17])([O:6][CH3:7])[O:4][CH3:5]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CO[Si](CCc1ccccn1)(OC)OC
Solvent: CCOC(C)=O
Product: CO[Si](CCc1cccc[n+]1C)(OC)OC
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
5.0 g of 2-(trimethoxysilylethyl)pyridine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 5.4 g of methyl trifluoromethanesulfonate was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, 2-(trimethoxysilylethyl)pyridine and methyl trifluoromethanesulfonate as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylethylmethylpyridinium trifluoromethanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13](Cl)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([NH2:37])[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.Cl>C(O)(C)C.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([NH:37][C:25]4[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[C:23]([Cl:22])[CH:24]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a 4-Chloro-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.08 g, 9.40 mmol, 1.05 equiv) in 40 mL of isopropyl alcohol solution was added 3-Chloro-4-(pyridin-2-ylmethoxy)phenylamine (2.10 g, 9.0 mmol, 1 equiv) at rt. 4 N HCl in dioxane (0.1 mL) was added to the reaction mixture to accelerate the reaction. The reaction mixture was heated at 80° C. for 16 h. The mixture was allowed to cool to rt then filtered and washed with IPA (50 mL). DCM (100 mL) and sat. sodium bicarbonate (100 mL) were added to the solid. The mixture was stirred at rt for 1 h before separated the layers. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.50 g of crude material. The crude material was purified by flash chromatography (50% THF/DCM) to yield a light yellow (3.60 g, 6.87 mmol, 76%) as product. 1H-NMR (DMSO-d6) δ 9.32 (broad s, 1H), 8.67 (d, J=4.0 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 8.05 (t, 1H), 7.79 (d, J=2.7 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.53 (t, 1H), 7.24 (d, J=8.9 Hz, 1H), 5.35 (s, 2H), 4.66 (s, 2H), 3.66 (t, 2H), 3.19 (t, 2H), 1.43 (s, 9H); LCMS RT=3.39 min, [M+H]+=524.0.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Li+]>ClCCl>[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
In accordance with the method of “Helvetica Chimica Acta”, 2002, vol. 85, no. 11, p. 3616-3623, triethylamine was added under ice-cooling to a mixture of trans-cinnamic acid chloride, (S)-4-benzyl-2-oxazolidinone, lithium chloride and dichloromethane, and then stirred at room temperature for 3Hours. Thereafter, (4S)-4-benzyl-3-[(2E)-3-phenylprop-2-enoyl]-1,3-oxazolidin-2-one was obtained by purifying it in the standard method. FP: 308.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=O)[O:12][C:10](=O)[CH2:9][CH2:8]1.[Cl-].[Al+3].[Cl-].[Cl-].[NH2:18][NH2:19]>C(O)C>[Br:1][C:2]1[S:3][C:4]([N:18]2[C:10](=[O:12])[CH2:9][CH2:8][CH:7]=[N:19]2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)O1
Reactant: NN
Reactant: Brc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Product: O=C1CCC=NN1c1ccc(Br)s1

Procedure:
(5-Bromo-2-thienyl)-1,4,5,6-tetrahydropyridazin-6-one was prepared as in Example 41 condensing 2-bromothiophene and succinic anhydride with aluminum chloride followed by reaction with hydrazine in ethanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][N:11]1[CH2:13][C:14]([O:16]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.B(F)(F)F.[CH3:31][CH2:32][O:33]CC.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl.CN(C1C=CN=CC=1)C>[C:32]([N:11]1[CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][N:24]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[C:14](=[O:16])[CH2:13]1)(=[O:33])[CH3:31]
Reactant: COC(=O)CN1CC1COCc1ccccc1
Reactant: NCc1ccc(F)cc1
Reactant: CCOCC
Agent: CN(C)c1ccncc1
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1COCc1ccccc1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of methyl {2-[(benzyloxy)methyl]aziridin-1-yl}acetate (0.4 g, 1.7 mmol), 4-fluorobenzylamine (0.38 g, 3.3 mmol), and boron trifluoride etherate (50 μL) was heated in a sealed glass tube at 95° C. for 68 h (Bull. Chem. Soc. Jpn., 1986, 59, 321). The resulting mixture was dissolved in dichloromethane (50 mL), cooled to 0° C., and treated with a mixture of triethylamine (0.95 mL, 6.8 mmol), DMAP (21 mg, 0.17 mmol), and acetic anhydride (0.48 mL, 5.1 mmol). The mixture was stirred at room temperature overnight, and extracted successively with saturated aqueous solution of sodium bicarbonate, dilute aqueous HCl, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 2% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title piperazinone.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1.C(Cl)(Cl)Cl.CC(C)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:63]([CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:69])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)CCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
A solution of 300 mg (0.35 mmole) of taxol, 500 mg (4.2 mmole) of succinic anhydride and 10 mg of DMAP in 4 mL of DMF is heated at 85° C. for 10 h (single spot by TLC using silica, chloroform/acetone, 9:1). With the use of the same procedure as for 2'-succinyltaxol above, the crude product is isolated, and chromatographed on 5 g of silica using toluene/10-50% acetone. This gave 300 mg (68%) of crystalline material: mp 180°-1° C.; [a] -30.1° (c=1.05, EtOH); Anal. (C H NO ) C,H,N.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)CCl.O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:34]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[CH:43]=[N:42][CH:41]=[CH:40]3)=[O:35])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][CH:19]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH2:25][NH:26][C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[C:34]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[CH:43]=[N:42][CH:41]=[CH:40]3)=[O:35])=[CH:22][CH:23]=1)=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Reaction time: 8 h

Procedure:
To 2,4-dimethylbenzoic acid in pyridine was added EDC, DMAP, and tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139), and the solution was capped and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E145).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][CH2:22][C@:23]([CH3:28])([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C@:23]([CH:25]1[CH2:27][CH2:26]1)([OH:24])[CH3:28])=[O:9]
Reactant: C[C@@](O)(CN)C1CC1
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: C[C@@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (S)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, MS (ISP) 465.0, 467.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1N1C(=O)c2ccccc2C1=O
Temperature: 23 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a solution of trans-3-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.78 g, 8.28 mmol) (WO 01/87838), phthalimide (1.46 g, 9.94 mmol) and TPP-resin (4.14 g) in anhydrous THF (30 ml) at 23° C. was added DIAD (2.4 ml, 12.4 mmol). The reaction mixture was stirred at 23° C. for 48 h. then the resin was filtered off and the filtrate was concentrated under reduced pressure to give an oil. The crude oil was purified by flash chromatography using silica gel (0-50% EtOAc-Heptane) which gave the title compound VIIa (1.6 g, 47% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O.CCO>[CH2:1]([O:8][CH2:9][C:10]1[NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[N:21][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccnc1NC(=O)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(COCc2ccccc2)nc2ncccc12
Yield: 18.7 %

Procedure:
2-(2-Benzyloxy-acetylamino)-nicotinamide (76 mg, 0.3 mmol) in H2O/EtOH (4 ml, 1:1) was stirred with sodium carbonate (28 mg, 0.3 mmol) at reflux for 2 hours. Water was added, the phases were separated and the inorganic layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo to yield 2-benzyloxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one (15 mg, 21%) as a white solid, MS (m/e): 268.1 [M+].
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:1][C:2]3[O:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1nc2ccccc2o1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccccc4o3)C(=O)O)cc2)cc1

Procedure:
Example 27 is prepared from 2-mercaptobenzoxazole and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.4 %

Procedure:
1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (4.81 g) was dissolved in pyridine (48 ml), added with p-toluenesulfonyl chloride (9.0 g) and triethylamine (6.7 ml) and stirred at room temperature for 17 hours. The reaction mixture was added with cold water (500 ml) and stirred for 2 hours, and then the produced crystals were collected by filtration. These crystals were purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 6.49 g of the title compound. Yield: 76%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: NCCCO
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCCCO)n2n1)c1cccnc1
Temperature: 120 °C
Yield: 41.3 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-amino-1-propanol (56 μL; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as an off-white solid (22 mg, 40%). HPLC, Rt: 2.05 min. (purity 96.2%). LC/MS, M+(ESI): 380.8, M−(ESI): 378.9.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]#[CH:18]>C(#N)C.C1(C)C=CC=CC=1>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:17]#[CH:16]
Reactant: OCc1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 4-hydroxyl-benzyl alcohol 13 (2.5 g, 20 mmol) in acetonitrile (50 mL), K2CO3 (3.96 g, 200 mol %) was added at room temperature (see Scheme 4). After stirring for 1 h, the mixture was treated dropwise with an 80 wt % solution of propargyl bromide in toluene (3.27 g, 110 mol %) and the reaction mixture was heated to 50° C. for 48 h, cooled, filtered and concentrated under vacuum. The residue was purified by flash chromatography using an eluent of 100% to 30% hexane in AcOEt. Evaporation of the collected fractions gave propargyl ether 14 as a yellow liquid (3.12 g, 95.5%): 1H NMR (CDCl3) δ (ppm): 7.28 (d, 2H, Ph-H), 6.96 (d, 2H, Ph-H), 4.69 (d, 2H, PhCH2), 4.57 (s, 2H, CCH2O), 2.54 (t, 1H, OH), 2.39 (s, 1H, CH); 13C NMR (CD3OD) δ (ppm): 157.4, 134.53, 128.97, 115.34, 78.97, 76.04, 65.10, 56.24. Anal. Calcd for C10H10O2: C, 74.07; H, 6.17. Found: C, 73.64; H, 6.03.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23]O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:25])([CH3:26])[CH2:22][CH2:23][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
To a solution of 5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-ol (F15, 75 mg), phthalimide (93 mg) and triphenylphosphine (165 mg) in tetrahydrofuran (3.5 mL), a 1.9 mol/L solution of diisopropyl azodicarboxylate in toluene (332 μL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 92 to 52% hexane in ethyl acetate) to obtain 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-yl)isoindoline-1,3-dione (F16, 129 mg) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[Pt].C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>[CH3:10][CH:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(N)cc1C
Reactant: CCCCCC(C)=O
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Product: CCCCCC(C)Nc1ccc(C)c(C)c1
Reaction time: 0.58 h
Yield: 99.4 %

Procedure:
3,4-Xylidine (24.2 grams; 0.2 mole), 2-heptanone (50.2 grams, 0.44 mole), 2-naphthalenesulfonic acid (0.9 g) and 5% of platinum on carbon (1.2 gms) were charged to a Parr reaction bottle and treated with hydrogen at 70° C. and a hydrogen pressure of 41-60 psig. The theoretical amount of hydrogen was consumed within 15 minutes. The mixture was held an additional 35 minutes, producing 43.6 g of N-2-heptyl-3,4-xylidine. The above sample analyzed 100% pure, corresponding to a yield of 99%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>COC(O)C.CCOCC>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Reactant: Nc1cccc(Br)c1
Agent: COC(C)O
Solvent: CCOCC
Product: COc1ccc2c(Nc3cccc(Br)c3)c(C#N)cnc2c1
Yield: 33.2 %

Procedure:
A solution of 2.97 g (13.6 mmol) of 4-chloro-7-methoxy -3-quinolinecarbonitrile and 4.67 g (27.2 mmol) of 3-bromo aniline in 76 ml of methoxyethanol was refluxed under nitrogen for 5 hours. The solution was cooled and diluted with ether. Solid was collected and washed with ether. The solid was stirred with a hot mixture of ethyl acetate and sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was recrystallized from a chloroform-ethyl acetate mixture giving 1.6 g of 4-[(3-bromophenyl)amino]-7-methoxy -3-quinolinecarbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 354.1, 356.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1.[Cl:37]CCC1C=CC2C(=CC=CC=2)C=1>C(O)C>[ClH:37].[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][CH2:25][N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: BrCCc1ccc2ccccc2c1
Reactant: ClCCc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cl
Product: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1
Yield: 59.8 %

Procedure:
In two different preparations, 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine is reacted, in the presence of triethylamine, with 2-(2-bromoethyl)naphthalene (PREPARATION A) and respectively with 2-(2-chloroethyl)naphthalene (PREPARATION B) in ethanol under reflux for 20 hours. The reaction mixtures of the two preparations were concentrated, the residue was taken up with ethyl ether and the ether solution, which was filtered and washed with water, was dried and evaporated. The residue was taken up with a solution of gaseous hydrochloric acid in isopropanol to give 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, which was crystallized from ethanol.