Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:13]3[CH:12]([C:16]([O:18]C)=[O:17])[CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+].O.Cl>O1CCCC1>[N:1]1([C:6]2[CH:15]=[CH:14][C:13]3[CH:12]([C:16]([OH:18])=[O:17])[CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C1CCCc2nc(-n3cnnn3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCc2nc(-n3cnnn3)ccc21
Reaction time: 1 h

Procedure:
Methyl 2-(1H-tetrazol-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxylate (1.04 g, 4.01 mmol) and lithium hydroxide (0.202 g, 4.81 mmol) were stirred in a mixture of tetrahydrofuran (10 ml)/water (10.00 ml) for 75 mins. The tlc showed some 20% starting material so more LiOH (50 mg, 1.19 mmol) was added and stirred for another 1 hr. The reaction was adjusted with 2N HCl (3 ml, 6 mmol) to pH 4-5 then extracted with ethyl acetate 2×. The ethyl acetate layers were combined and dried over Na2SO4, filtered and evaporated to dryness to yield 2-(1H-tetrazol-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxylic acid. 1H-NMR (600 MHz, CDCl3): δ ppm 9.53 (s, 1H), 7.85-7.89 (q, 2H), 3.945 (t, J=5.46 Hz, 1H), 3.01-3.05 (m, 1H), 2.90-2.96 (m, 1H), 2.29-2.44 (m, 1H), 2.04-2.13 (m, 2H), 1.95-2.01 (m, 1H); LC-MS: (M+1)-28=218.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1.COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[CH3:26][N:27]1[C:31]([S:32][CH2:1][O:2][C:3](=[O:6])[CH3:4])=[N:30][N:29]=[N:28]1.[CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5]
Reactant: Cn1nnnc1S
Agent: COC(=O)CO
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCSc1nnnn1C
Reaction time: 2 h

Procedure:
After glycolic acid methyl ester (300 mg, 3.33 mmol), triphenylphosphine (1052 mg, 4.00 mmol), 1-methyl-5-mercapto-1H-tetrazole (465 mg, 4.00 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (937 mg, 4.00 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using ethyl acetate (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 70% ethyl acetate-hexane solution) to give acetic acid (1-methyl-1H-tetrazole-5-ylsulfanyl)methyl ester as a colorless oily substance (549 mg, yield: 88%/glycolic acid methyl ester).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33]>CC#N>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:32]([C:24]3[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=3[CH2:22][CH2:21][O:20][CH3:19])(=[O:33])=[O:34])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: COCCc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COCCc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.59 g, 3.9 mmol) and N-methylmorpholine (2.53 g, 25 mmol) in MeCN (70 mL) was added 2-(2-methoxyethyl)-4-nitrobenzene-1-sulfonyl chloride (1.4 g, 5 mmol) in MeCN (20 mL) at 0° C., then the solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, and ethyl acetate and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 to 0:1) to give N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-methoxyethyl)-4-nitrobenzene sulfonamide (1 g, yield 50%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.CC(C)([O-])C.[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([CH:34]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2(/[CH:34]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: O=CC1(c2ccc(F)cc2)CCCCC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1(c2ccc(F)cc2)CCCCC1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (0.714 mL, 3.57 mmol) in 10 mL of THF at 0° C. was added 1 M potassium tert-butoxide in THF (3.57 mL, 3.57 mmol) dropwise, and the mixture was stirred for 15 mins at the same temperature. Then a solution of 1-(4-fluorophenyl)cyclohexanecarbaldehyde (Intermediate I-7A, 368 mg, 1.784 mmol) in 3 mL of THF was added dropwise, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with brine, dried over sodium sulfate and evaporated to give an oily residue which was purified by Combiflash (80 g silica gel) eluting with hexane followed by 5:95 EtOAc-hexane to give the desired (E)-ethyl 3-(1-(4-fluorophenyl)cyclohexyl)acrylate (453 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (2H, dd, J=9.02, 5.28 Hz), 7.01 (2H, t, J=8.80 Hz), 6.95 (1H, d, J=16.07 Hz), 5.60 (1H, d, J=16.07 Hz), 4.16 (2H, q, J=7.26 Hz), 1.99-2.08 (2H, m), 1.85-1.94 (2H, m), 1.39-1.62 (6H, m), 1.27 (3H, t, J=7.15 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#CC1(CNc2cccc(Br)n2)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: N#CC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A mixture of 4-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate S, 410 mg, 1.384 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (362.2 mg, 2.07 mmol), PdCl2(dppf).CH2Cl2 adduct (113 mg, 0.14 mmol), DME (5 Ml) and 2 M aqueous Na2CO2 (1.75 Ml, 3.5 mmol) was sealed and stirred at 110° C. for 20 min using microwave reactor. After cooling to room temperature the mixture was extracted with EtOAc (35 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 24 g, EtOAc/hexane=5/100 to 50/50] to provide 4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (360 mg, 75% yield). LCMS (m/z): 347 [M+H]+; retention time=0.814 min.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:39][C:40]1[CH:53]=[CH:52][C:43]([C:44]2[CH:45]=[CH:46][C:47]([CH3:51])=[C:48]([Pb+3])[CH:49]=2)=[CH:42][CH:41]=1.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]2[CH:45]=[CH:46][C:47]([CH3:51])=[C:48]([CH:4]3[C:3](=[O:12])[CH:2]4[CH:6]([CH:7]5[O:10][CH:1]4[CH:9]=[CH:8]5)[C:5]3=[O:11])[CH:49]=2)=[CH:52][CH:53]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Agent: CC(=O)[O-]
Agent: Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (374 mg, 2.3 mmol) and phenanthroline (610 mg, 5 mmol) under an atmosphere of nitrogen is added dry toluene (20 ml) and 4′-chloro-4-methylbiphen-3-yllead triacetate (2.0 g, 3.4 mmol). The reaction mixture is heated at reflux for 3.5 hours, then cooled to room temperature, acidified to pH1 with 2N aqueous hydrochloric acid (20 ml), ethyl acetate (20 ml) added and the mixture is filtered to remove solids. The filtrate is poured into a separating funnel and extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4′-chloro-4-methylbiphenyl-3-yl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione.
Reaction SMILES: [N+:1]([C:4]1([CH3:13])[CH2:10][N:9]([CH3:11])NCC(C)[CH2:5]1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1([CH3:13])[CH2:10][N:9]([CH3:11])[CH2:4][CH2:10][N:9]([CH3:11])[CH2:5]1
Reactant: CC1CNN(C)CC(C)([N+](=O)[O-])C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN1CCN(C)CC(C)(N)C1
Yield: 144.4 %

Procedure:
6-Nitro-1,4,6-trimethyldiazacycloheptane (13.1 g, 70 mmol) was was dissolved in absolute ethanol (20 ml) and 2 spatulas of Raney nickel added. The mixture was hydrogenated at approx. 1.1 atmospheres hydrogen pressure until no more hydrogen was taken up. It was filtered over a small pad of Celite and the filtrate evaporated and distilled to give the free amine as a colourless oil (7.95 g, 72%) b.p.>70° C./0.1 mm. IR (film) 3348 (s), 2945 (s), 2813 (s), 1670 (m), 1538 (m), 1462 (s), 1376 (m), 1284 (m), 1093 (s) cm−1. 1H NMR (CDCl3) δ 1.00 s(3H), 2.32 s(6H), 2.28 and 2.44 and 2.63, 3 m (10H including N—H). 13C NMR (CDCl3) δ 26.37, 48.91, 52.54, 60.35, 71.17. MS (FAB+) 158.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:15][C:16]3[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:17]=3[S:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH2:13][CH3:14]
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2N)cc1
Product: CCCc1ccc2c(Nc3cc(C(F)(F)F)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 2g (50 mg, 0.242 mmol) was reacted with the product from Example 35a (79.0 mg, 0.242 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the ditrifluoroacetic acid salt (10.5 mg, 10%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H), 1.81-1.92 (m, J=7.35 Hz, 2H), 2.07 (s, 3H), 3.01 (t, J=7.54 Hz, 2H), 6.44 (d, J=6.99 Hz, 1H), 7.11 (d, J=8.46 Hz, 1H), 7.42-7.49 (m, J=8.46 Hz, 2H), 7.69 (d, J=8.82 Hz, 2H), 7.78 (dd, J=8.82, 1.47 Hz, 1H), 7.87 (d, J=8.82 Hz, 1H), 7.91 (d, J=1.10 Hz, 1H), 8.52 (d, J=6.99 Hz, 1H), 9.03 (d, J=8.46 Hz, 1H), 11.14 (s, 1H); MS (ESI+) m/z 497 (M+H)+, ESI− m/z 495 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:19](O)=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.Cl.[CH2:24]([NH2:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:19]([NH:26][CH2:24][CH3:25])=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C(=O)O
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A mixture of 4-chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxylic acid (250 mg, 0.76 mmol), ethylamine hydrochloride (94 mg, 1.1 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.51 g, 1.1 mmol) in N,N-dimethylformamide (4 mL) was stirred at rt for 10 min. To the resulting mixture was added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol). After stirred at rt overnight, the reaction was quenched with water, extracted with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, and then concentrated to dry. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product (185 mg, 68%). LCMS calculated for C18H19ClF2NO2 (M+H)+: m/z=354.1; Found: 354.0.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH3:9][O:10][C:11](=[O:25])[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16].C(Br)C=C.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:9][O:10][C:11](=[O:25])[CH:12]([CH2:8][CH:6]=[CH2:7])[CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)CC(CC(=O)O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)C(CC(=O)O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a cooled (-78° C.) solution of LDA (7.1 mL, 2.0 M, 14.2 mmol) in 50 mL THF was added a solution of 3-(3-fluoro-phenyl)-pentanedioic acid monomethyl ester (2-4) (1.58 g, 6.58 mmol) in 10 mL THF gradually. The mixture was stirred for 40 min, treated with allyl bromide (1.71 mL, 19.7 mmol) at -78° C. and stirred overnight while it was warmed to room temperature. It was then concentrated and diluted with 20 mL CH2Cl2 and 15 mL EtOH. To the resulting solution was added EDAC (1.88 g, 9.87 mmol) and DMAP (25 mg, 0.02 mmol). After stirring for 5 hr, the reaction was quenched with 20 mL 10% NaHCO3 and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide 2-5 as an oil, which was further purified using flash silica chromatography (Hexane/EtOAc, 4:1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Cl)c(F)c(Cl)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)c(Cl)c2c1=O
Temperature: 0 °C
Yield: 100.5 %

Procedure:
5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux in a mixture of 38 ml of acetic acid, 30 ml of water and 4.3 ml of concentrated sulphuric acid for 2.5 hours. After cooling, the mixture is poured into 250 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 4.8 g of 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 277°-278° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CS(C)=O>[Cl:28][CH2:27][CH2:26][CH2:25][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(C#N)(CCCCl)Sc2ccc(C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.39 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile in 21 mL of dimethyl sulfoxide, under an argon atmosphere with stirring, is added 0.336 g of 60% sodium hydride in oil. This mixture is stirred for 1.5 hours. To the resulting solution is added 1.32 g of 1-bromo-3-chloropropane and this reaction mixture is stirred for 3 hours and is next poured into 100 mL of ice water. This mixture is twice extracted with diethyl ether and the combined organic extracts dried with magnesium sulfate. The organic solution is filtered, and concentrated in vacuo to give the desired compound as a golden oil.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCOCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C[Sn](C)(C)c1ccccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
In a 25 mL pear shaped flask was placed 5-iodo-2′-deoxyuridine (0.354 g, 1.0 mmol), 2-trimethylstannylpyridine (0.84 g, 3.5 mmol), Bis (triphenylphosphine)-palladium (II) chloride (0.070 g, 0.1 mmol), and anhydrous 1,4-dioxane (15 mL). The reaction was heated at 60° C. for 15 hrs then at 90° C. for 1 h. The solvent was evaporated and the residue purified by silica gel chromatography (10% CH3OH in CH2Cl2 (1% NH3)) to yield 0.253 g (83%) of the title compound as a white solid m.p. 201-203° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[CH3:23]OC(OC)(C)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:23])[CH2:6][CH2:5]1
Reactant: COC(C)(C)OC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reaction time: 8 h

Procedure:
10.0 g of 11β-fluoroandrost-4-ene-3,17-dione [U.S. Pat. No. 3,966,713 (1976)] is stirred under reflux with 60 ml of dimethoxypropane and 1.0 g of pyridinium-4-toluenesulfonate. After 8 hours, 1 ml of pyridine is added, the mixture is diluted with ethyl acetate, washed neutral with water, and dried. The crude product is chromatographed on silica gel with an acetone-hexane gradient. Yield: 7.8 g of 11β-fluoro-3-methoxyandrosta-3,5-dien-17-one as a foam.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:2][CH2:3][Cl:4])[N:10]=[CH:9]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: ClCCn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
1-Bromo-2-chloroethane (2.9 mL, 35 mmol) was added to a suspension of 5-bromo-1H-indazole (4.302 g, 21.95 mmol) and Cs2CO3 (28.56 g, 87.81 mmol) in DMSO (50 mL) under N2. The resulting suspension was stirred at 25° C. for 6 h. H2O (50 mL) was added, and the resulting suspension was cooled in an ice bath. The suspension was filtered, and the solid was dried under reduced pressure to afford a pink powder. Flash chromatography on silica gel (19:1 to 5:2 hexanes/EtOAc) gave the title compound (3.094 g, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.00 (br s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.50 (dd, J=9.0, 1.5 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 4.68 (t, J=6.3 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:26])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.Cl.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:26])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To an ice cold solution of 1.5 g (0.0043 mol) of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)-ethenyl]pyrido[2,3-d]pyrimidine in 40 mL of N-methylpyrrolidone containing 1.4 mL of N-methylmorpholine was added 1.72 g (0.0064 mol) of phenyl N-phenylphosphoramidochloridate in a single portion. The resulting mixture was stirred at 0° C. for 30 minutes. Diethyl L-glutamate hydrochloride (1.53 g, 0.0064 mol) was then added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residual solid triturated with 50 mL of 1N aqueous sodium carbonate. The mixture was filtered and the collected solid dissolved in 20 mL of chloroform. The chloroform solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness and chromatographed on silica gel. Elution with chloroform:methanol (95:5) gave 1.52 g (66%) of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoyl)-L-glutamate mp>250° C.; NMR (CDCl3Me2SO-d6) delta 1.15-1.45 (2t, 6H, J=6 Hz), 2.0-2.65 (m, 4H), 2.3 (s, 3H), 4.0-4.35 (2q, 4H, J=6 Hz), 4.5-4.75 (m, 1H), 6.7, 6.9 (AB q, 2H, J=15 Hz), 7.33, 7.84 (AB q, 4H, J=9 Hz), 8.25-8.38 (m, 2H), 8.62 (d, 1H, J=2Hz), 11.5-12.5 (br, 2H); IR (Nujol) 3320, 3150, 1730, 1680, 1630, 1600 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:23])[CH3:22])[CH:16]=3)[CH:14]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[O-:30][C:31]#[N:32].[Na+]>O>[C:21]([C:17]1[CH:16]=[C:15]([C:13]2[C:12]([O:24][CH3:25])=[CH:11][CH:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([NH2:32])=[O:30])=[CH:7][CH:6]=3)[CH:14]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(Nc2ccc(N)cc2)cc1-c1cccc(C(C)=O)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Nc2ccc(NC(N)=O)cc2)cc1-c1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 1-[5′-(4-amino-phenylamino)-2′-methoxy-biphenyl-3-yl]-ethanone synthesized above (free base) (60.0 mg, 0.180 mmol), water (600 μL), acetic acid (300 μL) and sodium cyanate (46.8 mg, 0.720 mmol). The mixture was stirred at room temperature for 4 hours and then water (20 mL) was added followed by an P-traction with (2×30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The crude material was purified by column utilizing 75% acetone/DCM as the eluent to produce 32 mg of [4-(3′-acetyl-6-methoxy-biphenyl-3-ylamino)-phenyl]-urea (P-268) as a light brown solid in 47% yield. MS (APCI+): 376.1 (M+1); LC-MS: 94%.