Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][NH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:38]>CO>[ClH:38].[ClH:38].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][NH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 64.9 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.30 g.), conc. hydrochloric acid (0.14 g.) and methanol (3.5 ml.) was stirred at room temperature for 7 hours. After concentrating the resultant solution in vacuo, the residue was pulverized with a mixture of diisopropyl ether (10 ml.) and methanol (10 ml.). The precipitates were collected by filtration to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 0.21 g.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O:11][C:12](=O)[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[C:19]=1[F:25])[C:14](=O)[CH3:15])C>O>[F:25][C:19]1[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:13]1[C:12](=[O:11])[O:1][C:2]2[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][C:7]=2[C:14]=1[CH3:15]
Reactant: CCOC(=O)C(Cc1cccc(N)c1F)C(C)=O
Reactant: Oc1cccc(S)c1
Solvent: O
Product: Cc1c(Cc2cccc(N)c2F)c(=O)oc2cc(S)ccc12
Temperature: 70 °C
Yield: 6.3 %

Procedure:
152 mg (1.21 mmol) of 3-hydroxy-benzenethiol and 153 mg (0.60 mmol) of 2-(2-fluoro-3-aminobenzyl)-3-oxobutanoic acid ethyl ester were added to polyphosphoric acid (6 g), and the mixture was stirred and heated at 70° C. for 2.5 hours. Water was then added to the reaction mixture, and the precipitated solid was filtered out. The obtained solid was purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 20:1) to yield 12 mg (1%) of compound 5d-0-4S1 as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5](B(O)O)=[C:4]([O:12][CH3:13])[CH:3]=1.I[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: COc1cc(F)c(F)cc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
4,5-Difluoro-2-methoxyphenyl-boronic acid (8.8 g, 46.82 mmol) and 4-iodophenol (6.86 g, 31.21 mmol) were suspended in 165 ml of DMF. H2O (40 mL) was added and the mixture was degassed with argon. Finely ground potassium carbonate (13 g, 93.63 mmol) and tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.29 mmol) were added. The reaction was stirred at 80-85° C. for 1 hr under argon and cooled. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried and solvents were evaporated. The crude product was purified by flash chromatography, eluting with 0-8% ethyl acetate in hexanes to yield 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (6.58 g, 89.3%). LR-MS (ES) calculated for C13H10F2O2, 236.22; found m/z 235 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N:10]=[C:11]=[O:12])[CH:3]=1.C(N(CCCC)CCCC)CCC.O(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11](=[O:12])[NH:10][CH:9]=[CH:8]2
Reactant: O=C=N/C=C/c1cccc(Br)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: O=c1[nH]ccc2cc(Br)ccc12
Temperature: 210 °C
Yield: 30.4 %

Procedure:
A solution of (E)-1-bromo-3-(2-isocyanatovinyl)benzene (100 g, 0.44 mol) in toluene (200 mL) was added dropwise to a mixture of tributylamine (100 mL) and oxydibenzene (500 mL) at 190° C. After the addition, the mixture was heated at 210° C. for another two hours. Thin layer chromatography (petroleum ether/ethyl acetate=1:1) indicated the reaction was complete. The mixture was cooled to room temperature, filtered, and the solid was washed with ethyl acetate (50 mL×3). The solid was dried under vacuum to give crude 6-bromoisoquinolin-1(2H)-one (30 g, 30%) as a light yellow solid, which was used in the next step directly.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=O)[CH:7]=[CH:8][CH:9]=1)=O.[NH3:27]>CO>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:27][C:3](=[O:2])[C:5]3[N:6]([CH:7]=[CH:8][CH:9]=3)[CH:10]=2)=[CH:14][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: O=c1[nH]c(-c2ccc(OCc3ccccc3)cc2)cn2cccc12
Temperature: 25 °C

Procedure:
A suspension of 100 mg (0.286 mmol) 1-[2-(4-benzyloxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester in a 7 M solution of ammonia in methanol is irradiated in a microwave apparatus at 90° C. for 18 h. The reaction mixture is cooled to room temperature and evaporated. The residue is chromatographed on a silica gel column with petrolether/ethylacetate as eluent to give 3-(4-benzyloxy-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as beige crystals; HPLC/MS 2.26 min (A), [M+H] 317.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C@:9]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:40])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:8])([OH:3])=[O:2].C(N/C(=N/C(C)C)/O[CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])(C)C>C1COCC1.CCOC(C)=O>[CH3:27][C@:24]12[C@@:23]3([CH3:28])[C@@H:14]([C@:15]4([CH3:40])[C@@H:20]([CH2:21][CH2:22]3)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])=[O:36])=[CH:38][CH:39]=3)=[CH:17][CH2:16]4)[CH2:13][CH2:12][C@@H:11]1[C@H:10]1[C@H:41]([C:44]([CH3:46])=[CH2:45])[CH2:42][CH2:43][C@:9]1([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:1](=[O:3])[O:2][CH2:53][CH2:54][Si:55]([CH3:56])([CH3:57])[CH3:58])[CH2:26][CH2:25]2
Reactant: CC(C)/N=C(/NC(C)C)OCC[Si](C)(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-carboxyethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (35 mg, 0.056 mmol) and (Z)-2-(trimethylsilyl)ethyl N,N′-diisopropylcarbamimidate (27.2 mg, 0.111 mmol) was refluxed in THF (1 mL) for 4 h. Then the mixture was placed at room temperature for 16 h. TLC showed no starting material and a new less polar product Rf=0.4 in 10% AcOEt/Hex. The solvent was removed in vacuo. The residue was dissolved in methylene chloride and purified in silica gel (0-10% AcOEt/Hex) to afford 2-(trimethylsilyl)ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (43 mg, 0.049 mmol, 89% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.93 (d, J=8.28 Hz, 2H), 7.20 (d, J=8.03 Hz, 2H), 6.24 (t, J=6.02 Hz, 1H), 5.30 (d, J=4.77 Hz, 1H), 4.76 (d, J=1.51 Hz, 1H), 4.61 (s, 1H), 4.49-4.37 (m, 2H), 4.28-4.17 (m, 2H), 3.65-3.52 (m, 1H), 3.52-3.39 (m, 1H), 3.15 (td, J=10.85, 3.64 Hz, 1H), 2.63-2.43 (m, 3H), 2.11 (dd, J=17.19, 6.40 Hz, 1H), 2.02-1.90 (m, 2H), 1.80-1.04 (m, 22H), 1.70 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.93 (s, 6H), 0.10 (s, 9H), 0.06 (s, 9H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:10]1)=O)(C)(C)C.[ClH:34]>C(O)C>[ClH:34].[NH2:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:10]1
Reactant: CC1COc2c(N3C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CCO
Product: CC1COc2c(N3C[C@@H](N)[C@@H](C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10-(cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (0.55 g) in ethanol (8 ml) and ethanolic hydrochloride solution (10 ml) was stirred for 2 hours at room temperature and then concentrated. To the resulting residue was added ethanol and the resulting precipitate was collected by filtration and then washed with hot ethanol to give the title compound (0.5 g) as yellowish powder, mp 298° C. (decompd.)
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH:8][CH2:9][CH:10]=[CH2:11])=[O:7])(=O)[CH3:2].O=P(Cl)(Cl)Cl.Cl.[OH-].[Na+]>O>[CH3:2][C:1]1[O:7][C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:5][N:4]=1
Reactant: C=CCNC(=O)NNC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCNc1nnc(C)o1

Procedure:
1-Acetyl-4-n-propyl semicarbazide (35 g, 0.22 mol) prepared by method (a) above, was refluxed with POCl3 (150 ml) for 2 hours, until no more HCl was evolved. Excess POCl3 was taken off by a water pump and the mixture poured into 200 ml. iced water and neutralized with 50% NaOH to pH 7. Red oil was extracted with dichloromethane (2×180 ml), dried, filtered and evaporated down to yield an oil which was distilled in a vigreux flask to yield the title compound as a pink liquid which crystallised upon standing to a solid. (m.p. 46.5°-47.5° C.).
Reaction SMILES: [CH2:1]([C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O1CCBN1.CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.S(C)C.Cl>O1CCCC1.C(OCC)C.CO>[CH2:1]([C:6]1[C@H:7]([OH:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CCCC1=O
Agent: B1CCON1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCCC1=CCC[C@H]1O
Yield: 87.5 %

Procedure:
A solution of 2-pentyl-2-cyclopenten-1-one (9.12 g, 60 mmole) in 140 ml of tetrahydrofurane (THF) was treated with an oxazaborolidine represented above, namely (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (16.7 ml; 0.36 M in toluene, 6.0 mmole; see D. J. Mathre, ref. cited). A solution of BH3.S(CH3)2 (3.30 ml=2.64 g, 34.8 mmole) in THF (60 ml) was added dropwise at 0° over 1 h. The reaction was stopped with 3 ml of methanol (development of H2), followed by ethyl ether and 5% HCl. The organic phase, which had been washed to neutrality (2× with water and 1× with brine), was separated and the solvent evaporated. 9.5 g of a crude product were obtained, which was distilled in a bulb-to-bulb apparatus (oven temp. 60°/11 Pa), to give 8.1 g of (+)-(1R)-2-pentyl-2-cyclopenten-1-ol (yield 89%).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[CH:7]1([C:10]2[NH:11][C:12]([I:16])=[C:13](I)[N:14]=2)[CH2:9][CH2:8]1>O.CCO>[CH:7]1([C:10]2[NH:14][CH:13]=[C:12]([I:16])[N:11]=2)[CH2:9][CH2:8]1
Reactant: Ic1nc(C2CC2)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1c[nH]c(C2CC2)n1
Yield: 72.6 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of sodium sulfite (11.3 g, 89.7 mmol) in H2O/EtOH (30/15 mL). 2-Cyclopropyl-4,5-diiodo-1H-imidazole (compound 44.2, 3.8 g, 10.6 mmol) was added and the resulting solution was heated at reflux overnight. The reaction was cooled and the volatiles were removed under reduced pressure. The solids were collected by filtration to yield 1.8 g (73%) of the title compound as a light brown solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:11]1([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:20]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=4[C:18]([C:17]([F:16])([F:28])[F:27])=[N:19]3)=[CH:4][CH:5]=2)=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=C(c1ccc(CBr)cc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 53.8 %

Procedure:
A mixture of 1-{[4-(bromomethyl)phenyl]carbonyl}pyrrolidine (84 mg, 0.31 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (60 mg, 0.32 mmol), and potassium carbonate (87 mg, 0.63 mmol) in N,N-dimethylformamide (2 ml) was stirred at 140° C. in a microwave reactor for 10 minutes. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was dried over sodium sulphate and reduced to minimum volume under reduced pressure. The crude product was purified using mass directed auto-prep to give the title compound as a pale yellow oil (63 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]I)=[CH:8][O:9][C:5]=2[CH:4]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CCI)coc2c1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc2c(CCN3CCN(c4cccc5cccnc45)CC3)coc2c1

Procedure:
A mixture of 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetate:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as yellow oil. Yield: 120 mg (31%); (M+H): 388; 1HNMR (400 MHz, CDCl3): δ□8.82˜8.81 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.05˜8.02 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.44˜6.35 (m, 8H); 3.9 (s, 3H); 3.60˜2.70 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21]([N:31]2[CH2:32][CH2:33][CH2:34][C@@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:35])[CH2:30]2)[CH:20]=[CH:19][C:18]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(Br)ccc2Cl)nc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c2)C1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
Method 2—Step c 2-(5-bromo-2-chloro-phenyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (1.50 g, 3.69 mmol), (R)-(−)-Nipecotic acid ethyl ester (0.75 g, 4.79 mmol) and cesium carbonate (6.00 g, 18.43 mmol) were placed into a dry Schlenk tube under nitrogen. At the same time palladium acetate (0.17 g, 0.74 mmol), and BINAP (0.71 g, 1.11 mmol) were placed into a dry 7 mL vial under nitrogen. Then dry toluene (5 mL) was added and the mixture was stirred 20 minutes under nitrogen before being added to the first flask. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, filtered off, and the insoluble material was washed with EtOAC (3×10 mL). The organic solution was concentrated under reduced pressure and crude was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to cyclohexane 4: AcOEt 1) to afford 1.33 g of the title compound (74%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Fc1ccccc1Br
Reactant: C#CCCCCCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a solution of 2-bromofluorobenzene (49 g), 1-dodecyne (210 ml) triethylamine (210 ml), and tetrahydrofuran (50 ml) was added (bis)triphenylphosphine palladium(II)chloride (532 mg) and copper(l)iodide (532 mg). The reaction mixture was warmed to 55° C. and stirred for 24 hr. The mixture was allowed to cool to room temperature and filtered. The precipitate was washed with ethyl acetate, and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled to afford 11 g (15%) of product, bp 175-180° C. at 1 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:31]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:29][CH:30]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccccc5)cc4)cc3)n(C)c(=O)c12

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (395 mg), benzyl bromide (0.13 ml) and potassium carbonate (408 mg) in DMF (5 ml) was stirred at 60° C. for 1 hour. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (346 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[S:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(#N)C>[C:13]1([S:10]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2][N:40]2[CH2:41][CH2:42][N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)[CH2:38][CH2:39]2)(=[O:12])=[O:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=S(=O)(c1cccc2ccccc12)N1CCCCC1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1cccc2ccccc12)N1CCCCC1CCN1CCN(c2ccccn2)CC1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 2-(2-chloroethyl)-1-(naphthalene-1-sulfonyl)piperidine (D1) (250 mg) in acetonitrile (20 ml) was added sodium iodide (12 mg), potassium carbonate (108 mg) and 1-(2-pyridyl)piperazine (143 ul). The mixture was heated at reflux overnight. After cooling to room temperature the residue was chromatographed on silica eluting with 5% methanol in dichloromethane to afford the title compound as an oil (301 mg, 87%). Trituration with diethyl ether afforded a foam. MH+ 465
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:45]2[CH:44]=[CH:43][C:42]([N:39]3[CH2:38][CH2:37][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:41][CH2:40]3)=[CH:47][CH:46]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) in dioxane (2 ml) was added (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (73 mg, 0.24 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.01 mmol) and 159 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 75 mg (74% yield) as a white solid. Purity 99%.