Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([F:30])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:30][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1

Procedure:
A mixture of 6-bromo-9H-purine (14.5 mg, 0.0727 mmol), (3R)-1-[7-(1-aminoethyl)-5-fluoroquinolin-8-yl]pyrrolidin-3-ol (10 mg, 0.04 mmol), and N,N-diisopropylethylamine (0.013 mL, 0.073 mmol) in isopropyl alcohol (0.1 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. First peak retention time 1.32 minutes, LCMS calculated for C20H21FN7O (M+H)+: m/z=394.2; Found: 394.2. Second peak retention time 1.40 minutes, LCMS calculated for C20H21FN7O (M+H)+: m/z=394.2; Found: 394.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:10]([O:17][C:18]1[CH:43]=[CH:42][CH:41]=[CH:40][C:19]=1[CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:10]([O:17][C:18]1[CH:43]=[CH:42][CH:41]=[CH:40][C:19]=1[CH:20]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C(=Cc1ccccc1OCc1ccccc1)c1ccccc1
Yield: 75.7 %

Procedure:
5.09 g of benzaldehyde and 26.1 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) were dissolved in 100 ml of acetonitrile, with heating. 8.04 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were then added dropwise to the solution at 80° C., whilst stirring, and the resulting mixture was stirred at the same temperature for 40 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was concentrated by distillation under reduced pressure, and 100 ml of a 2:1 by volume mixture of hexane and ethyl acetate were added to the resulting residue, and the mixture was agitated. Insoluble materials were filtered off, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 30:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 10.4 g (yield 76%) of 2-benzyloxystilbene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9]C(=O)C)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OCc1ccnc(C)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CO)ccn1
Reaction time: 24 h
Yield: 93.2 %

Procedure:
Acetic acid 2-methyl-pyridin-4-ylmethyl ester (5.1 g, 31 mmol) was stirred with ammonium hydroxide (10 ml) in methanol (25 ml) at room temperature. After 24 hr., the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA) to afford 3.56 g (94%) of (2-methyl-pyridin-4-yl)-methanol as a pale yellow solid. m.p. 58-59° C. 1H NMR (200 MHz, CDCl3) δ 2.45 (3H, s), 4.66 (2H, s), 7.06 (1H, d, J=5.2 Hz), 7.14 (1H, s), 8.25 (1H, d, J=5.2 Hz).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[NH2:25][CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1.[C:37]([NH:40][CH2:41][C:42](O)=[O:43])(=[O:39])[CH3:38]>CN(C=O)C>[C:37]([NH:40][CH2:41][C:42]([NH:25][CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:43])(=[O:39])[CH3:38]
Reactant: CC(=O)NCC(=O)O
Reactant: NCCc1c[nH]c2ccccc12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)NCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
Diphenylphosphorylazide (5.8 ml, 27.5 ml) and triethylamine (3.85 ml, 27.5 ml) were added in succession to a mixture of tryptamine (4.32 g, 27 mmol) and N-acetylglycine (3.3 g, 28 mmol) in DMF (100 ml) cooled to 0° C. The mixture was stirred under nitrogen at ambient temperature for 12 h, then the solvent was eliminated under reduced pressure. The residue obtained was flash chromatographed on silica gel to produce the expected product (m=5.5 g, 21 mmol), giving a yield of 78%.
Reaction SMILES: [Br-].ClC1C=C[C:6]([C:9](=O)[CH2:10][N+:11]2[CH:16]=[CH:15][C:14](C(C)C)=[CH:13][CH:12]=2)=CC=1.CC(C)(CC#CC(=O)C(C)(C)C)C(OCC)=O>CN(C=O)C>[CH2:6]1[C:12]2[N:11]([CH2:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9]1
Reactant: CC(C)c1cc[n+](CC(=O)c2ccc(Cl)cc2)cc1
Agent: CCOC(=O)C(C)(C)CC#CC(=O)C(C)(C)C
Agent: [Br-]
Solvent: CN(C)C=O
Product: C1=CCN2CCCC2=C1
Temperature: 70 °C
Yield: 64.2 %

Procedure:
To a solution of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(propan-2-yl)pyridinium bromide (1.55 g, 4.37 mmol) and ethyl 2,2,7,7-tetramethyl-6-oxooct-4-ynoate (1.04 g, 4.37 mmol) in DMF (8.0 mL) is added TEA (0.9 mL, 6.56 mmol). The mixture is heated at 70° C. for 24 h then cooled to 23° C. and partitioned between Et2O and water. The organics are washed with water, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 10% EtOAc in hexanes) gives dihydroindolizine (340 mg, 15%) that is dissolved in MeOH (10 mL) and treated with sodium borohydride (25 mg, 0.664 mmol). The mixture is stirred for 10 min then treated with water, extracted with EtOAc, dried with MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in MeOH (4 mL) and 6M aqueous NaOH (4 mL) and heated at 70° C. for 1 h then cooled to 23° C. The mixture is acidified to pH=1 with concentrated aqueous HCl, then partitioned between CH2Cl2 and brine. The organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by reverse phase HPLC gives the title compound (44 mg, 14%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19]Br)=[O:15])[C:12](=[O:21])[NH:11][C:10]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:37]3[CH2:36][CH2:35][N:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])[CH2:39][CH2:38]3)=[O:15])[C:12](=[O:21])[NH:11][C:10]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1[nH]c(=O)n(C(=O)NCCCBr)c1-c1ccc(F)c(F)c1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1[nH]c(=O)n(C(=O)NCCCN2CCN(c3ccccc3OC)CC2)c1-c1ccc(F)c(F)c1
Yield: 2 %

Procedure:
A mixture of 5-(3,4-difluorophenyl)-2,3-dihydro-4-methoxycarbonyl-1-(3-bromoprop-1-yl)aminocarbonyl-2(1H)-imidazolone (386 mg, 0.92 mmol), 4-(2-methoxyphenyl)piperazine (353 mg, 1.84 mmol), potassium carbonate (382 mg, 2.76 mmol) and sodium iodide (138 mg, 0.92 mmol) in dioxane (15 mL) was heated at reflux for 24 hours and then concentrated. The residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was flash chromatographed over silica gel eluting with EtOAc/MeOH (9:1) to give the desired product (2% yield). Hydrochloride salt: yellow solid; m.p. 122-124° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2ccc(C=O)cc2)nc1
Temperature: 110 °C
Yield: 122.1 %

Procedure:
A mixture of 2-bromo-5-methylpyridine (2 g), (4-formylphenyl)boronic acid (3.5 g), tetrakis(triphenylphosphine)palladium(0) (0.672 g), and potassium carbonate (4.8 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (15 mL) was added at room temperature. The reaction mixture was heated at 110° C. for 6 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 20% ethyl acetate in hexane as eluant to afford the title compound (2.8 g).
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.S([O-])(=O)(=O)C.[I-:22].[Na+].C(=O)(O)[O-].[Na+]>CC(C)=O>[I:22][CH2:6][C:7]#[C:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCC#CCOc1ccccc1
Reactant: [I-]
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: ICC#CCOc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
By following the esterification method of part B of this preparation, the preceding compound was converted into 4-phenoxybut-2-yn-1-ol methanesulfonate in almost quantitative yield. The foregoing crude mesylate was dissolved in 15 ml of acetone and treated with a solution of 5.55 g (0.037 mol) of sodium iodide and 1.049 g (0.0123 mol) of sodium bicarbonate in 30 ml of acetone. The reaction mixture was stirred for 1 hour at room temperature and then the solvent was removed under reduced pressure. The residue was diluted with water and extracted with methylene chloride; the organic extracts were dried and evaporated. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (95:5) as eluant, to yield 1-iodo-4-phenoxybut-2-yne.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[CH3:18][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33](N(OC)C)=[O:34])[N:23]=1)([CH3:21])[CH3:20]>O1CCCC1.C1CCCCC1>[CH3:21][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)=[O:34])[N:23]=1)([CH3:18])[CH3:20]
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C1CCCCC1
Product: CC(C)(C)c1nc(C(=O)c2nccs2)nc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of diisopropylamine (0.39 mL, 4.2 mmol) in tetrahydrofuran (8 mL) at -78° C. under nitrogen atmosphere is added a 2.1M solution of n-butyllithium (2.0 mL, 4.2 mmol) in cyclohexane. This mixture is stirred at -78° C. for 1 hour and thiazole (0.3 mL, 4.2 mmol) added. After stirring 1 hour at -78° C., the reaction mixture is warmed to ~0° C. and stirred 0.5 hours. The mixture is cooled to -78° and 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (0.50 g, 1.7 mmol) in a mixture of tetrahydrofuran (5 mL) and N,N,N'N'-tetramethylethylenediamine (2 mL). After stirring 1 hour at 78° C., the resulting mixture is warmed to room temperature and stirred 16 hours. The mixture is then quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts are washed with water and brine. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The organic residue is purified by flash chromatography (SiO2, 10% methanol/dichloromethane) followed by recrystallization from ethyl acetate and hexane to give 0.30 g (53%) of the title compound, mp 181°-184° C.
Reaction SMILES: BrC1([O:12][C:13]2C=[CH:17][CH:16]=[CH:15][CH:14]=2)COC(C)(C)OC1(C)C.NC1C=CC=CC=1.C1(NC2C=CC=CC=2)C=CC=CC=1.[Br:39][C:40]1[CH:52]=[CH:51][C:50]2[C:49]3[C:44](=[CH:45][C:46](Br)=[CH:47][CH:48]=3)[C:43](CC)(CC)[C:42]=2[CH:41]=1>>[Br:39][C:40]1[CH:41]=[C:42]2[C:50]([C:49]3[CH:48]=[C:47]([CH2:46][CH3:45])[C:14]([CH:13]=[O:12])=[C:15]([CH2:16][CH3:17])[C:44]=3[CH2:43]2)=[CH:51][CH:52]=1
Reactant: CC1(C)OCC(Br)(Oc2ccccc2)C(C)(C)O1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: Nc1ccccc1
Product: CCc1cc2c(c(CC)c1C=O)Cc1cc(Br)ccc1-2
Yield: 93 %

Procedure:
The convergent synthesis of AF-452-6OH (compound 9 in Scheme 1) was accomplished in two parallel sequences followed by a converging sequence: (i) a 4-step sequence to the protected 3-O-alkylated diphenylamine intermediate, (ii) a 3-step sequence to the tris(7-bromofluorene(triazine intermediate 7 and (ii) a 2-step sequence to AF-452-6OH (8). Briefly, the first sequence was started with tris-1,1,1-(hydroxymethyl)ethane, which was first protected as an acetonide derivative, i.e. 2,2,5-trimethyl-5-hydroxymethyl-1,3-dioxane (compound 1) in either reaction as indicated in Scheme 1, as reactions (i) or (ii). A Mitsunobu reaction of 1 with 3-bromophenol furnished the corresponding bromophenoxy-methyltrimethyl-1,3-dioxane (2) in 85% yield [Scheme 1, reaction (iii)]. The same compound could also be obtained in 59% yield from a copper-catalyzed reaction between 3-bromoiodobenzene and 1 [Scheme 1, reaction (iv)]. Compound 2 was aminated with aniline to produce the diphenylamine intermediate 3 [Scheme 1, reaction (v)]. In the second sequence, 2,7-dibromo-9,9-diethylfluorene (4) was first monoformylated to form 7-bromodiethylfluorene-2-aldehyde (5), which was then converted to the nitrile intermediate (6) in 93% yield [Scheme 1, reactions (vi) and (viii), respectively]. A less satisfactory conversion of the aldehyde intermediate 5 to the nitrile intermediate 6 via an hydroxyl-imine intermediate was also conducted [49% yield, Scheme 1, reaction (vii)]. The nitrile intermediate 6 was subsequently and catalytically trimerized in trifluoromethanesulfonic acid to afford the tribromo-1,3,5-triazine intermediate (7) in 95% yield [Scheme 1, reaction (ix)]. Covalently joining the triazine (7) component with the diphenylamine component (3) with the assistance of a Pd-catalyzed amination gave the precursor chromophore protected as an acetonide 8, [Scheme 1, reaction (x)]. Removal of the acetone protecting groups from 8 was accomplished by mixing and stirring 8 together with Dowex-50Wx2 (acid-form) resin, and the desired product, AF-452-6OH (9), was obtained in 90% yield [Scheme 1, reaction (xi)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[I:20][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(Cc2ccsc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1ccc(Cc2ccsc2I)cc1
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of 3-(4-fluorophenylmethyl)thiophene (1.16 g, 6.04 mmol) in 1:1 CHCl3 /methanol was added N-iodosuccinimide (1.70 g, 7.53 mmol). The reaction mixture was stirred for 3 hours, and then was diluted with CH2Cl2. The organic phase was extracted with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 1.83 g of 2-iodo-3-(4fluorophenylmethyl)thiophene which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([F:24])[C:5]([N+:21]([O-])=O)=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].[H][H]>C(O)C.O1CCCC1.[Ni].ClCCl>[NH2:21][C:5]1[C:4]([F:24])=[C:3]([F:25])[C:2]([Cl:1])=[C:11]2[C:6]=1[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]2[CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c(N)c2c1=O
Yield: 86.2 %

Procedure:
A suspension of 21.7 g (58.2 mmol) of ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-nitro-4-oxo-3-quinolinecarboxylate in 300 ml of ethanol and 300 ml of tetrahydrofuran was catalytically reduced using 3 g of Raney nickel in a hydrogen atmosphere of 50 psi. After twelve hours the mixture was diluted with dichloromethane and the catalyst was removed by filtration. The filtrate was concentrated to give 17.2 g of the title compound.
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].S(=O)(=O)(O)O.[CH3:31]O>>[C:1]([O:25][CH3:31])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Reaction time: 1 h
Yield: 74 %

Procedure:
10,12- Tricosadiynoic acid (3.0 g, 0.0084 mol), methanol (15 ml) and concentrated sulfuric acid (0.8 ml) were heated to reflux and stirred for 1 hour. The cooled mixture was taken up in either (40 ml) and washed with 10% NaHCO3 (20 ml) and water (20 ml), and the organic phase was dried (MgSO4). Evaporation of the solvent gave 2.68 g (74%) of the title compound. 1H NMR (60 MHz, CDCl3): δ 0.98 (m, 3H, CH3CH2), 1.28 (m, 28H, CH2), 2.25 (m, 6H, CH2), 3.70 (s, 3H, CH2O).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(O[CH:14](OCCC)[N:15]([CH3:17])[CH3:16])CC>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCCOC(OCCC)N(C)C
Reactant: CC(=O)c1cccnc1
Product: CN(C)C=CC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of 25 g of 3-acetylpyridine and 35 ml of N,N-dimethylformamide dipropylacetal was heated at 100° C. for 6 hours. The mixture was concentrated in vacuo and the residue crystallized, giving 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O1CCCC1>[C:14]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)(=[O:16])[CH3:15]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1cnc(-c2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-phenylimidazole in 40 ml of tetrahydrofuran was added portionwise 1.66 g of 50% sodium hydride. After stirring for 20 minutes, 2.46 ml of acetyl chloride was added over 10 minutes and the reaction mixture allowed to stir overnight at room temperature. The reaction was filtered and the filtrate concentrated to give 4 g of crude product which was purified by chromatographing on 150 g of silica gel using 5% methanol in chloroform as eluent, 2.88 g.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][C:11](=[O:31])[C@@H:12]([NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)[N:18]=[C:17]([C:28]([NH2:30])=[O:29])[CH:16]=1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:10][C:11](=[O:31])[CH:12]([NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][CH:24]([O:27][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:25][CH2:26]2)[N:18]=[C:17]([C:28]([NH2:30])=[O:29])[CH:16]=1)[CH3:13]
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(N2CCC(O)CC2)n1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(Nc1cc(C(N)=O)nc(N2CCC(Oc3ccc(C#N)cc3)CC2)n1)C(N)=O
Temperature: 160 °C

Procedure:
A mixture of 4-fluorobenzonitrile (121 mg, 1 mmol), compound 37-7 (308 mg, 1 mmol), and Cs2CO3 (326 mg, 1 mmol) in DMF (2 mL) was heated at 160° C. in a microwave (Biotage initiator) for 20 minutes. The mixture was extracted with EtOAc (2×20 mL) and dried over MgSO4. After the removal of ethyl acetate via rotary evaporator the residue was subjected to flash chromatography using DCM/MeOH as the eluent to give S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-cyanophenoxy)piperidin-1-yl)pyrimidine-4-carboxamide (Cpd. No. 100) as a white solid (150 mg). 1H NMR (CD3OD) δ 7.55-7.65 (m, 2H), 7.12 (m, 2H), 6.40 (s, 1H), 4.80 (m, 1H), 4.30 (m, 1H), 3.95 (m, 2H), 3.68 (m, 2H), 1.98 (m, 2H), 1.75 (m, 2H), 1.40 (d, 3H). LC/MS: m/z=410 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[N:13]1([C:19]([S:21][CH3:22])=[S:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:16]1[CH2:17][CH2:18][N:13]([C:19]([S:21][CH3:22])=[S:20])[CH2:14][CH2:15]1
Reactant: COc1cccc(CCl)c1OC
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CN2CCN(C(=S)SC)CC2)c1OC
Yield: 40.5 %

Procedure:
To 20 ml of ethanol were added 1.0 g (5.36 mmol) of 2,3-dimethoxybenzyl chloride, 943 mg (5.36 mmol.) of methyl 1-piperazinecarbodithioate and 568mg (5.36 mmol.) of sodium carbonate. The obtained mixture was refluxed under heating for 2 hours. Ethanol was distilled off under reduced pressure. To the residue was added water. The aqueous mixture was extracted with 30 ml of ether. The ether portion was shaken together with 5 ml of 3-N hydrochloric acid. An oil which was insoluble in either portion and the aqueous portion were combined. The combined mixture was extracted with ether, after addition of 20 ml of 1-N aqueous sodium hydroxide solution. The ether extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Theresidue was recrystallized from ethanol to give 708 mg of the desired compound, m.p. 110°-111° C., yield 40.5%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[O:15])=[CH:9][C:8]=1[CH3:16])(=O)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[O:15])=[CH:9][C:8]=2[CH3:16])=[CH:22][CH:21]=1
Reactant: Cc1cc(C=O)cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)cc(C)c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 4-formyl-2,6-dimethylphenyl trifluoromethanesulfonate (2.17 g), 4-chlorophenylboronic acid (1.80 g), tris(dibenzylideneacetone)dipalladium (0.282 g), 2,6-dimethoxy-2′-(dicyclohexylphosphino)biphenyl (0.505 g), sodium carbonate (2.45 g), toluene (34.5 mL) and water (11.5 mL) was stirred at 100° C. overnight under a nitrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound.