Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:18][CH:17]=2)[CH:15]=1.[CH3:30][N:31]1[CH2:36][CH:35]=[C:34](B(O)O)[CH2:33][CH2:32]1.[F-].[Cs+]>O1CCOCC1.O.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>[CH3:30][N:31]1[CH2:32][CH:33]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)[CH2:35][CH2:36]1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Reactant: CN1CC=C(B(O)O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC=C(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Temperature: 150 °C

Procedure:
A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), 1-Methyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (Boron Molecular, 221 mg; 0.99 mmol; 3.0 eq.), PdCl2(PPh3)2 (23 mg; 0.03 mmol; 0.10 eq.), cesium fluoride (151 mg; 0.99 mmol; 3.0 eq.) in dioxane (3 mL) and water (1.5 mL) was degassed with nitrogen flow and heat in MW at 150° C. for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three time with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as a yellow powder. 1H NMR (300 MHz, DMSO) δ 13.36 (brs, 1H), 9.39 (s, 1H), 8.31 (s, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.78-7.47 (m, 4H), 6.32-6.11 (m, 1H), 3.84-3.49 (m, 6H), 3.46-3.25 (m, 2H), 3.11-2.98 (m, 2H), 2.71-2.58 (m, 4H), 2.30 (s, 3H). HPLC (Condition A): Rt 2.22 min (purity 94.5%). MS (ESI+): 470.3, MS (ESI−): 468.3.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:29]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCN(Cc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.110 g, 0.37 mmol) in methylene chloride (3.7 mL) were added N-hexyl-benzylamine (0.079 g, 0.41 mmol) and DMAP (0.045 g, 0.37 mmol) followed by 1-ethyl-3-(3dimethylaminopropyl) carbodiimide hydrochloride (0.071 g, 0.37 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.139 g (80%) of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]=2[N+:23]([O-:24])=[O:22])[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc2nc(Cl)nc(Cl)c2c([N+](=O)[O-])c1OC
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a suspension of 2,4-dichloro-6,7-dimethoxyquinazoline (30.0 g, 0.12 mol) in acetonitrile (550 ml) at 0° C. was added nitronium tetrafluoroborate (25.9 g, 0.19 mol) portionwise over 15 min. The reaction was stirred for 0.75 h and then evaporated under reduced pressure. The resulting solid was suspended in a mixture of saturated aqueous sodium bicarbonate and EtOAc and the solid filtered, dissolved in CH2Cl2, dried over MgSO4 and evaporated to give the subtitle compound as a pale yellow solid (27 g). Further material was obtained by separating the organic layer of the filtrate, washing with H2O (1×), saturated brine (1×), drying over MgSO4 and filtering through a pad of silica. Subsequent evaporation under reduced pressure, trituration with EtOAc and filtration gave the subtitle compound as a pale yellow solid (3.9 g, overall yield 88%). Rf 0.24 (ether/hexane 1/1, v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:15]=2)=[CH:23][CH:24]=1
Reactant: Nc1ccncc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Nc3ccncc3)n2)cc(OC)c1OC
Yield: 10 %

Procedure:
Using Method R, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 4-aminopyridine, 25 mg of title compound were obtained. Yield: 10%. 1H NMR (250 MHz, DMSO-d6) δ 3.64 (s, 3 H), 3.68 (s, 6 H), 6.83 (s, 2 H), 7.55 (d, 2 H, J=6.3 Hz), 7.62 (s, 1 H), 7.69 (s, 1 H), 8.25 (d, 2 H, J=6.3 Hz), 9.23 (s, 1 H), 9.66 (s, 1 H). 13C NMR (62.5 MHz, DMSO-d6) δ 55.66, 60.14, 97.52, 112.07, 122.57, 123.96, 132.67, 136.40, 147.39, 148.88, 149.83, 150.18, 152.93. m/z 354.2 [(M+H)+ calcd for C18H19N5O3 353.2].
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][CH:10]1[CH2:11][CH2:12][O:7][CH2:8][CH2:9]1
Reactant: CC(C)(O)CN
Reactant: O=C1CCOCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(O)CNC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.75 g of 1-amino-2-methylpropan-2-ol are dissolved in 20 ml of MeOH. 1.71 ml of glacial acetic acid are added dropwise under an inert atmosphere. 2 g of tetrahydropyran-4-one in 10 ml of MeOH are added, the mixture is stirred for 30 minutes at room temperature and 1.98 g of sodium cyanoborohydride are added. The resulting mixture is stirred under an inert atmosphere for 15 hours. The reaction medium is poured into saturated aqueous NaHCO3 solution (100 ml). The resulting mixture is stirred for 30 minutes and then extracted with 4 times 100 ml of DCM. The organic phase is dried over Na2SO4, filtered and evaporated without heating. The MeOH contained in the aqueous phase is evaporated off and the extraction, drying, filtration and evaporation operation is repeated 3 times. 2.8 g of 2-methyl-1-((tetrahydro-2H-pyran-4-yl)amino)propan-2-ol are recovered in total.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.IC>C1COCC1>[CH3:22][O:21][C:19]([C:16]1([CH3:1])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)=[O:20]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCOCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at −78° C., n-BuLi (25.2 ml, 1.6 M in heptane) is added. The reaction is removed from the bath and stirred for 10 min. It is then cooled to −78° C. again and methyl tetrahydro-2H-pyran-4-carboxylate (6.48 ml, 48.6 mmol) is added. After 30 min, iodomethane (6.07 ml, 97 mmol) is added and the reaction allowed to reach rt. The reaction is then quenched with 1 N HCl (200 mL) and extracted with EtOAc. The organic layer is dried and evaporated to give 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester. MS (ESI) m/z 159.3 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[N:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccon2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(CN2CCNCC2)no1

Procedure:
A solution of 0.84 g (3.2 mmol) of the title compound from Step B above in 5 mL dichloromethane and 5 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was carried forward without purification. LC/MS: m/z (ES) 168.1 (MH)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Reactant: Nc1cccc(Cl)c1
Product: Cc1ccc2ccnc(Nc3cccc(Cl)c3)c2n1

Procedure:
The title compound, MS: m/e=270.3/272.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 3-chloroaniline.
Reaction SMILES: [F:1][C:2]1[C:11]([C:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:30][Mg]Br>C1COCC1>[F:1][C:2]1[C:11]([C:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)([OH:13])[CH3:30])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[Mg]Br
Reactant: Cn1cc(-c2ccc3ncc(C(=O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ncc(C(C)(O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(5,7-Difluoro-quinolin-6-yl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanone (Stage 191.2, 666 mg, 1.706 mmol) was dissolved in THF (13 mL) and the mixture was cooled down to 0° C. with an ice bath. A solution of methylmagnesium bromide (1.4 M, 3.05 mL) was added slowly. The RM was stirred at 0° C. for 15 min then it was warmed up to rt. After 4 h stirring, more methylmagnesium bromide (1.4 M, 1.0 mL) was added and after 1 h stirring, the reaction was quenched with a few mL of water. The RM was mixed with 10% Na2CO3 solution and the aqueous layer was extracted with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was triturated with Et2O and the yellow solid was filtered off to give the title compound (tR 1.28 min (conditions 12), MH+=407).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]#[N:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O.O>C(#N)C>[Br:18][C:12]1[C:13]([F:14])=[C:8]([C:5]2[C:4]([C:16]#[N:17])=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([F:15])=[CH:10][CH:11]=1
Reactant: N#Cc1cc(F)ccc1-c1c(F)cccc1F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(F)ccc1-c1c(F)ccc(Br)c1F
Temperature: 70 °C
Reaction time: 7 h
Yield: 171.1 %

Procedure:
To a slurry of 4,2′,6′-trifluorobiphenyl-2-carbonitrile (5.0 g, 21.4 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (3.37 g, 11.8 mmol) in acetonitrile (45 ml) was added concentrated sulphuric acid (3.15 g, 32.2 mmol). The slurry was warmed to 70° C. and the resulting solution stirred for 7 h then stood at ambient temperature for 18 h. Water (45 ml) was added dropwise to the solution over 15 min. The layers were allowed to settle and the product rapidly crystallised. The slurry was left to stir for 0.5 h then filtered, washed with 1:1 acetonitrile/water (10 ml) and left to air-dry, which gave 3′-bromo-4,2′,6′-trifluorobiphenyl-2-carbonitrile (6.3 g, 94%) as a white solid: δH (360 I, CDCl3) 6.97-7.08 (1H, m), 7.38-7.54 (2H, m), 7.62-7.68 (1H, m).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>>[N:10]1[C:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[N:8][N:4]2[C:5]([N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14][CH2:13]3)=[CH:6][CH:7]=[CH:2][C:3]=12
Reactant: c1ccc2c(c1)CCCN2
Reactant: Clc1nc2c(Br)cccn2n1
Product: c1ccc2c(c1)CCCN2c1nc2cccc(N3CCCc4ccccc43)n2n1

Procedure:
1,1′-[1,2,4]triazolo[1,5-a]pyridine-2,5-diyldi-1,2,3,4-tetrahydroquinoline was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.15 mmol) and 1,2,3,4-tetrahydro-quinoline (274.0 mg, 2.04 mmol) in a manner analogous to Example 2d. Byproduct was isolated as a brown solid (0.033 g, 4%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.14 (d, J=8.2 Hz, 1H), 7.40-7.35 (m, 1H), 7.32-7.28 (m, 1H), 7.15-7.05 (m, 3H), 6.98 (t, J=7.5 Hz, 1H), 6.91-6.84 (m, 2H), 6.69-6.62 (m, 2H), 4.09-4.05 (m, 2H), 3.88-3.83 (m, 2H), 2.93 (t, J=6.4 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H), 2.10-1.80 (m, 4H). MS=382 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N:6]([CH2:10][CH3:11])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].[I-:23].[Na+]>C(#N)C>[I-:23].[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N+:6]([CH2:10][CH3:11])=[C:7]([CH3:9])[N:8]([CH2:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:4]=2[CH:3]=1
Reactant: CCn1c(C)nc2cc(Cl)c(Cl)cc21
Reactant: C[Si](C)(C)CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC[n+]1c(C)n(CCC[Si](C)(C)C)c2cc(Cl)c(Cl)cc21

Procedure:
5,6-Dichloro-1-ethyl-2-methylbenzimidazole (22.9 g, 0.10 moles), 3-chloropropyltrimethylsilane (15.0 g, 0.10 moles), and sodium iodide (15.0 g, 0.10 moles) were suspended in acetonitrile (200 ml) and with stirring the mixture was refluxed for 17 hours. It was filtered while hot to remove NaCl and the filtrate treated with ether (300 ml). Solid which precipitated was filtered off, washed with ether and dried. Yield 11.3 g (24%) mp 213°-5°. Additional crops were obtained by concentrating the filtrates and adding more ether. The mp of each crop was lower and less exact than the previous crop but all crops contained at least some product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH3:20])[C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][C:12]=1[CH3:20]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccc(F)cc2)oc1C
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of 667 mg (4.80 mmol) of 4-fluorobenzamide and 1.0 g (4.80 mmol) of methyl 4-bromo-3-oxo-pentanoate in 6 mL of dry toluene was heated at 120° C. for 16 h. The resulting dark slurry was cooled to rt, diluted with 10 mL of EtOAc, and washed with NaHCO3 (1×10 mL). The organic layer was separated, dried (MgSO4), and the solvents removed under reduced pressure. Purification of the material by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent to afford 308 mg of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) δ7.97 (m, 2H), 7.11 (m, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36(s, 3H).
Reaction SMILES: [NH:1]=[C:2]([CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5].[O:11]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[NH:1]=[C:2]([CH3:10])[CH:3]([C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])[C:21]([NH:20][C:18]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:19])=[S:22]
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: CCCOC(=O)CC(C)=N
Solvent: Cc1ccccc1
Product: CCCOC(=O)C(C(C)=N)C(=S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
A warm solution of n-propyl 3-iminobutyrate (18.2 g.) in toluene (75 ml.) was added to a stirred solution of phenoxycarbonyl isothiocyanate (22.8 g.) in toluene (75 ml.). The temperature of the mixture rose from 20° C. to 35° C. The mixture was then stirred for 1.5 hours at the ambient temperature, filtered and the residue washed with light petroleum (b.p. 40°-60° C.) to give 3-imino-2-n-propoxycarbonyl-N-phenoxycarbonylthiobutyramide (36 g.) in the form of an orange solid. This solid was dissolved in ethyl acetate (125 ml.) and treated at 2°-5° C. with a solution of bromine (0.7 ml.) in ethyl acetate (40 ml.) over 15 minutes. The mixture was stirred at the ambient temperature for 1.5 hours and then filtered to give 3-methyl-5-phenoxycarbonylamino-4-n-propoxycarbonylisothiazole hydrobromide (28 g.), m.p. 157°-163° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:14])C)[CH:8]=2)[O:3]1.[O:16]1CCOCC1.Cl[O-].[Na+].[OH-].[Na+]>O>[CH3:15][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:16])[CH:8]=2)[O:3]1
Reactant: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: C1COCCO1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: CC1(C)CCc2cc(C(=O)O)ccc2O1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A mixture of 5.8 g (28.4 mmol) of 2,2-dimethyl-6-acetylchroman (Compound 57), 75 ml of dioxane, 300 ml of 10% sodium hypochlorite solution and 50 ml of a 20% solution of NaOH in water was heated at 65° C. for 0.5 hour. The mixture was then treated with another 200 ml of 10% sodium hypochlorite solution and then heated at 65° C. for a further 65 hours. The mixture was cooled to room temperature and washed with ether. The aqueous layer was then treated with sodium metabisulphite solution until it was negative to the potassium iodide-starch test. The aqueous solution was then acidified to pH=4 with dilute H2SO4 and stored in the refrigerator for 48 hours. The solution was then diluted with water and extracted with ether. The ether layers were combined and washed with saturated NaCl solution and then dried (MgSO4). The solution was filtered and the solvent was removed in-vacuo to give the title compound as a white solid. PMR (CDCl3): & 1.36 (6H, s), 1.84 (2H, t, J~6.8 Hz), 6.81 (1H, d, J~8.4 Hz), 7.82-7.89 (2H, m). MS exact mass, m/e 206.0942 (calcd. for C12H14o3 206.0943).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(C)CC2)nc1
Temperature: 100 °C
Yield: 34.3 %

Procedure:
Methyl 2-chloropyrimidine-5-carboxylate (0.863 g, 5.0 mmol), N,N-diethylethanamine (0.697 ml, 5.00 mmol) and 1-methylpiperazine (0.565 ml, 5.09 mmol) were suspended in 2-propanol (10.00 ml) and sealed into a microwave tube. The reaction was heated to 100° C. for 10 mins in the microwave reactor and cooled to room temperature. The precipitate was collected by filtration, washed with EtOH (5 mL) and dried under vacuum to afford methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.405 g, 34.3%) as a white solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]#[CH:12].I[C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1.C1C=CC=CC=1.C(N(CC)CC)C>O=O.[Cu]I>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[C:14]([C:12]#[C:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:15]=[CH:16][C:17]=1[OH:24]
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: C#Cc1cc(OC)ccc1OC
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)c1cc(C#Cc2cc(OC)ccc2OC)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere 240 mg of 2,5-dimethoxyphenylacetylene and 493 mg of methyl 5-iodosalicylate are dissolved in 20 ml of oxygen-free and dry benzene. The mixture is treated with 85 mg of tetrakis (triphenylphosphine)palladium, 20 mg of copper(I)iodide and 450 mg of triethylamine, stirred at room temperature overnight and then poured onto 100 ml of aqueous pH 7 buffer. After extraction with ethyl acetate and purification by chromatography on silicagel, 5-[2-(2,5-dimethoxyphenyl)ethinyl]-2-hydroxybenzoic acid methyl ester is obtained (colorless crystals of M.P. 105°-108°).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7][CH3:8])[S:4][C:3]=1[C:9]([O:11]CC)=O.[CH:14]([NH2:16])=O>>[CH3:8][S:7][C:5]1[S:4][C:3]2[C:9](=[O:11])[NH:16][CH:14]=[N:1][C:2]=2[CH:6]=1
Reactant: NC=O
Reactant: CCOC(=O)c1sc(SC)cc1N
Product: CSc1cc2nc[nH]c(=O)c2s1
Temperature: 155 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of ethyl 3-amino-5-(methylthio)-thiophene-2-carboxylate (2 g) and formamide (20 mL) was stirred at 150-160° C. for 6 h. The reaction mixture was allowed to rt and poured into ice cold water. The solution was stirred for 15 min. and the precipitated solid was filtered, washed with ice cold water and dried to give the product as a light brown color solid (1.2 g, 61%), mp 216-218° C. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (1H, s), 8.11 (1H, s), 7.26 (1H, s), 2.68 (3H, s); LC-MS (negative ion mode): m/z 197 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccnc(-c2ccccc2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccnc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-phenylisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 417.21 g/mol.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:22]([OH:27])[OH:23])=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cnc(F)c(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round-bottomed flask, diisopropylamine (Aldrich, 1.40 mL, 9.99 mmol) was dissolved into THF (6 mL). nBuLi (Aldrich, 2.5 M in hexanes, 3.60 mL, 8.99 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min then cooled to −78° C. 2-fluoro-5-methoxypyridine (0.520 g, 4.09 mmol) in 4 mL of THF was added slowly, and the mixture was stirred at that temperature for 40 min. Triisopropyl borate (Aldrich, 2.07 mL, 8.99 mmol) in a total of 4 mL of THF was added slowly and the mixture was stirred at −78° C. for 5 min. The cold bath was removed and the reaction mixture was stirred at room temperature for 1 h. 1 N NaOH (20 mL) was added to the mixture to quench the reaction. The layers were separated and the aqueous phase was treated with 5N HCl to adjust the pH to around 5. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford 0.593 g of tan color solid. This material was used in the next step without further purification.