Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[N:23]([CH2:24]C(=C=O)OC)[N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[C:30]([O:33][CH2:34]C)(=[O:32])[CH3:31]>[Pd]>[NH2:11][C@@H:12]([CH2:17][CH2:18][C:19]1[N:23]([CH2:24][CH2:31][C:30]([O:33][CH3:34])=[O:32])[N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CCc1nnnn1CC(=C=O)OC)NC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COC(=O)CCn1nnnc1CC[C@H](N)C(=O)OC
Temperature: 24 °C
Reaction time: 4 h

Procedure:
To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-4-[1-(2-methoxy-carbonylethyl) tetrazol-5-yl]butyrate (0.233 g, 0.575 mmol) in ethyl acetate (25 ml) was added 10% Pd/C. (0.045 g). The resulting black mixture was degassed and then stirred at 24° C. for 4 hours under hydrogen. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to a colourless viscous oil that dried in vacuo over phosphorous pentoxide. There was thus obtained methyl (2S)-2-amino-4-[1-(2-methoxycarbonylethyl)tetrazol-5-yl]butyrate (0.146 g, 94%) as a colourless viscous oil. This was used in the next step without any further purification.
Reaction SMILES: O.Cl[C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=1[CH3:18].[C:19](=O)([O-:21])[O-:20].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(C)(C)C>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:5]1[C:4]([CH3:18])=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([CH3:12])(=[O:11])=[O:10])[C:19]([OH:21])=[O:20]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(Cl)c1C
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)O
Solvent: O
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Temperature: 160 °C
Yield: 96.9 %

Procedure:
12.5 mL of water was added to 237.5 mL of tert-butanol, then nitrogen gas was blown thereinto for 5 minutes to remove dissolved oxygen thereby to prepare a reaction solvent. Into a 500 mL autoclave, 50.0 g of 1-chloro-3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzene, 28.5 g of sodium carbonate, 1.5 g of 1,4-bis(diphenylphosphino)butane, the above reaction solvent, and 1.5 g of 5% Pd/C were introduced, and the autoclave was closed. With stirring, nitrogen flushing (5.0 MPa) was carried out twice, followed by flushing with carbon monoxide (5.0 MPa) twice. Finally, carbon monoxide was filled (2.5 MPa). By an electric furnace, the autoclave was heated to 160° C., followed by stirring for 7 hours (300 rps). After cooling to room temperature, carbon monoxide gas remaining in the autoclave was removed. The content was poured into water and ethyl acetate, and insolubles were filtered off by celite. Then, the filtrate was subjected to liquid separation, and the aqueous layer was washed twice with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (pH=1) and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (50.1 g). Further, the obtained solid was washed with 150 mL of hexane and then collected by filtration and dried under reduced pressure to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (48.1 g) as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.CCN(C(C)C)C(C)C.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39]>ClCCl.CN(C1C=CN=CC=1)C>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol) in dichloromethane (4 mL) was added DIEA (0.16 mL, 0.92 mmol) and DMAP (1.4 mg, 0.011 mmol) at 0° C., then a solution of 1-propanesulfonyl chloride (51 mg, 0.36 mmol) in dichloromethane (5 mL) was added. The resulting reaction mixture was stirred at 0° C. for 1 h and at room temperature overnight. The reaction mixture was concentrated. Purification by HPLC using acetonitrile/water gave the title compound (67 mg).
Reaction SMILES: P(Cl)(Cl)Cl.O[CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9].P(Cl)(Cl)[Cl:22].CN(C=O)C.C([O-])(O)=O.[Na+]>O.CC(OC)(C)C.CN(C=O)C>[Cl:22][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: ClP(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A 3-N 100 mL flask was charged with PCl3 (2.8 mL, 31.6 mmol) and dry DMF (32 mL) then stirred at RT for 1 h. In a separate 50 mL flask, farnesol (Ex-1B-5) (10.0 g, 45.2 mmol) and DMF (10 mL) was charged. The PCl3/DMF solution was then transferred to the farnesol, solution and the resulting dark orange solution was stirred for 1 h. The reaction was quenched by addition of solid NaHCO3 (2.5 g, 63.2 mmol). The solvent was removed by high vacuum rotary evaporation to yield an oily orange residue. To the residue was added MTBE (40 mL) and water (40 mL). The aqueous phase was washed with MTBE (3×20 mL). The MTBE layers were combined, washed with brine (2×20 mL), dried over MgSO4, filtered and finally concentrated by rotary evaporation to yield 1-chloro-3,7,11-trimethyl-dodeca-2,6,10-triene (Ex-1B-6) as a yellow oil (9.89 g, 92%). 1H NMR (400 MHz, CDCl3) δ (ppm): 5.47 (broad-t, J=8.3 Hz, 1H), 5.15-5.07 (m, 2H), 4.12 (d, J=8.1 Hz, 2H), 2.18-1.95 (m, 8H), 1.75 (s, 3H), 1.70 (s, 3H), 1.62 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH:26]=2)O1>>[S:25]1[C:21]2[CH:20]=[CH:19][C:18]([C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=3)=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: Oc1ccc(Br)cc1F
Product: Oc1ccc(-c2ccc3scnc3c2)cc1F

Procedure:
Compound 4-(benzo[d]thiazol-5-yl)-2-fluorophenol (W121) was prepared using the general procedure for Suzuki coupling reaction between 4-bromo-2-fluorophenol (57 mg, 0.3 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (78 mg, 0.3 mmol), as a white solid (45 mg, 61%). 1H NMR (400 MHz, acetone-d6) δ 9.27 (s, 1 H), 8.85 (s, 1 H), 8.28 (d, J=1.6 Hz, 1 H), 8.15 (d, J=8.4 Hz, 1 H), 7.75 (dd, J=8.4, 1.6 Hz 1 H), 7.55 (dd, J=12.4, 2.4 Hz, 1 H), 7.45 (m, 1 H), 7.12 (t, 9.2 Hz, 1 H); MS (ESI) m/z 246 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:50])([F:49])[CH2:26][C@@H:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:50])([F:49])[CH2:26][C@@H:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:30])[CH3:31])=[O:21])[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc(N)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To the material from Step 10 (81 mg, 0.113 mmol) and 10% palladium on carbon (11.99 mg, 0.011 mmol) was added ethyl acetate (1.3 mL). The reaction mixture was purged with nitrogen, and stirred under hydrogen (1 atm) overnight. Upon addition of DCM, the reaction mixture was filtered through celite, washed with dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) to afford 50 mg of the title compound as a colorless foam. LCMS (M+1)=689.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([CH:34]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(NCC)C.[CH2:41]([N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54])[C:42]#[CH:43]>[Pd](Cl)Cl.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:43]#[C:42][CH2:41][N:44]2[C:48](=[O:49])[C:47]3=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]3[C:45]2=[O:54])=[C:25]([C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1I
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g(4.2 mmole) of cuprous iodide, 68.8 g (0.21 mole) of 5-chloro- 2-iodobenzophenone, 200 ml of diethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargyl-phthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting precipitate was collected by filtration to give the crude product mp 130°-133° C. Recrystallization from acetone gave cream colored prisms, mp 148°-150° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+].C(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:29]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), acetaldehyde (0.15 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 33 mg (60%) of the title compound as a yellow solid. MS (ESI) m/z 503.3 (M+H)+1.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:30](=[O:31])[C:27]3[CH:28]=[CH:29][C:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(OC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-biphenylcarbonyl chloride (14 mg) and N,N-diisopropylethylamine (28 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]1[O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]OCCOCCOC1.CO[C:21]1C(O)=C[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31].BrCC(OCC)=[O:36]>>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([N+:30]([O-:32])=[O:31])[CH:21]=[C:17]([O:18][CH3:1])[C:16]=1[O:15][CH2:14][C:13]([O:12][CH2:11][CH3:10])=[O:36]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(O)c(OC)c([N+](=O)[O-])c1
Product: CCOC(=O)COc1c(OC)cc([N+](=O)[O-])cc1OC
Yield: 76.3 %

Procedure:
18-Crown-6 (1.069 g, 4.05 mmol), 2,5-dimethoxy-3-hydroxynitrobenzene (0.961 g, 4.05 mmol) and ethyl bromoacetate (0.449 ml, 4.05 mmol) were stirred at RT for 18 h. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography eluting with 10-15% EtOAc in Isohexanes to afford the title compound (881 mg, 76%). m/z 286 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH2:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([N:34]=[C:35]=[O:36])=[C:27]([CH:33]=1)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29].C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH:11][C:35]([NH:34][C:26]1[CH:25]=[CH:24][C:23]([Br:22])=[CH:33][C:27]=1[C:28](=[O:29])[N:30]([CH3:31])[CH3:32])=[O:36])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N=C=O
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Br)ccc1NC(=O)NCCN(C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 29.6 %

Procedure:
To a solution of (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (100 mg, 0.574 mmol) in DMF (2 mL) was added diisopropylethylamine (0.3 mL, 1.75 mmol) and 5-bromo-2-isocyanato-N,N-dimethyl-benzamide (154 mg, 0.572 mmol). The solution was stirred for 18 hours at 80° C. Ethyl acetate was added to the reaction mixture, and the combined mixture was washed 3 times with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was recrystallized from a mixture of ethyl acetate and dichloromethane to give 75 mg (30%) of {2-[3-(4-bromo-2-dimethylcarbamoyl-phenyl)-ureido]-ethyl}-methyl-carbamic acid tert-butyl ester. 1H-NMR (250 MHz, CDCl3) δ 11.0 (br s, 1H), 8.35 (d, J=9.1 mmol), 7.77 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=9.0 Hz, 1H), 3.45-3.55 (m, 5H), 2.97 (s, 6H), 2.86 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:13]([OH:14])=[C:12]([F:15])[C:11]([CH3:16])=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42](F)[CH:43]=1)[C:39]#[N:40]>C1COCC1.CS(C)=O.O>[Cl:7][C:8]1[C:13]([O:14][C:42]2[CH:41]=[C:38]([CH:37]=[C:36]([F:35])[CH:43]=2)[C:39]#[N:40])=[C:12]([F:15])[C:11]([CH3:16])=[CH:10][CH:9]=1
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cl)c(Oc2cc(F)cc(C#N)c2)c1F
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
KOtBu (6.23 ml of a 1M solution in THF, 6.23 mmol) was added to a solution of 6-chloro-2-fluoro-3-methylphenol (1.00 g, 6.23 mmol) and 18-CROWN-6 (0.823 g, 3.11 mmol) in DMSO (12 ml) at RT. After 20 mins, 3,5-difluorobenzonitrile (0.87 g, 6.23 mmol) was added and the solution was heated at 120° C. overnight. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (0-25% EtOAc/hexs) to provide 3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-5-fluorobenzonitrile (1.15 g, 66%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (dd, J=8.42, 1.46 Hz, 1H), 7.06-7.14 (m, 2H), 6.87-6.95 (m, 2H), 2.33 (d, J=2.11 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:43][C@@H:44]([CH2:49][OH:50])[CH2:45][CH:46]([CH3:48])[CH3:47]>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:43][C@@H:44]([CH2:49][OH:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: CC(C)C[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)NC(=O)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
5-Bromo-6-chloro-nicotinic acid (2.0 g, 8.46 mmol) was dissolved in DMA (20 mL). To the solution was added TBTU (3.1 g, 9.3 mmol), N,N-diisopropylethyl amine (7.4 mL, 42 mmol) and (D)-leucinol (1.1 g, 9.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (cyclohexane/ethyl acetate gradient) to yield 2.6 g of the title compound as a yellow oil, MS (ISP) 337.1 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-BOC-3-hydroxyazetidine (1.0 g, 5.77 mmol), 4-dimethylaminopyridine (7 mg, 0.058 mmol) and triethylamine (0.880 mL, 6.35 mmol) in DCM (15 mL) cooled at 0° C. was added dropwise methanesulfonyl chloride (0.45 mL, 5.77 mmol). The RM was stirred 18 h at rt, diluted with DCM, washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. 3-Methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester obtained as an oil was used directly in the next step. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g 5.57 mmol) in DMF (20 mL) stirred at 0° C. was added sodium hydride (55% in oil, 0.243 g, 5.57 mmol). After addition the mixture was stirred 1 h at rt, a solution of the above obtained 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 5.57 mmol) in DMF (3 mL) was added. The RM was stirred 30 min at rt, and then 3 h at 95° C. After cooling at rt the mixture was poured in ice water and extracted with EtOAc. The combined organic phases were washed with a solution of saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (with heptane and EtOAc as eluants) to afford the title compound as an oil (tR 4.33 min (conditions 3), MH+=350.1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:17]=[C:18]([OH:25])[C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1>CN(C=O)C>[CH2:2]([O:25][C:18]1[C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=[C:16]([Cl:15])[CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Cl)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
1-(Bromomethyl)benzene (7.905 ml, 66.46 mmol) was added to a mixture of cesium carbonate (21.65 g, 66.46 mmol) and 5-chloro-2-nitropyridin-3-ol (11.6 g, 66.46 mmol) in DMF (50 mL). The reaction mixture was stirred overnight at ambient temperature, then partitioned between ethyl acetate and water, washed with water and brine, dried, and concentrated to afford 3-(benzyloxy)-5-chloro-2-nitropyridine (16.0 g, 91.0% yield) as a light yellow powder. 1H NMR (CDCl3) δ 5.25 (s, 2H), 7.41 (m, 5H), 7.53 (s, 1H), 8.04 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1.O>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:17][CH2:16]2)[C:18]([C:20]2[CH:21]=[N:22][C:23]([N:36]3[CH:40]=[CH:39][N:38]=[CH:37]3)=[N:24][CH:25]=2)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-n3ccnc3)nc2)C2CC2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (3.00 g), ethyldiisopropylamine (1.97 mL) and 1H-imidazole (520 mg) in N-methyl-2-pyrrolidinon (10 mL) is stirred over night at 100° C. After cooling to room temperature, water is added and the precipitate is filtered off and dried. LC (method 9): tR=1.29 min; Mass spectrum (ESI+): m/z=413 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17](=[O:19])[CH2:16][NH:15][C:13]([C:7]1[C:8](=[O:12])[O:9][C:10]2[C:5]([C:6]=1[OH:20])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)=[O:14])[CH3:26]
Reactant: O=C(O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O

Procedure:
A mixture of [(7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid (3.209 g, 9.38 mmol) and thionyl chloride (2.05 mL, 28.1 mmol) in ethanol (75 mL) was refluxed for 2 h; then cooled, the precipitates were collected via filtration and washed with cold ethanol, air dried to give the desired product (3.153 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=17.5 (s, 1H), 9.5 (br, 1H), 7.88 (dd, 1H, J=0.6 Hz, 8.4 Hz), 7.5-7.2 (m, 2H), 4.32-4.18 (m, 4H), 1.32 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[CH2:14]([O:16][P:17]([O:21]CC)[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][P:17]([CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cnc(-c2ccccc2)o1
Product: CCOP(=O)(Cc1cnc(-c2ccccc2)o1)OCC
Yield: 59.8 %

Procedure:
5-Chloromethyl-2-phenyl oxazole (870 mgs, 4.50 mmol) and triethylphosphite (1.17 ml, 6.75 mmol) were heated at reflux for 3 h, cooled, the excess triethylphosphite removed under reduced pressure and the residue column chormatographed (0 to 5% MeOH/CH2Cl2, 10 g silica) to give the title compound (794 mgs, 2.69 mmol, 60%); δH (CDCl3) 1.30 (6H, t, J 7 Hz, OCH2CH3), 3.30 (2H, d, JP-H 22 Hz, CH2 --P) 4.10 (4H, m, OCHH2CH3), 7.00 (1H, d, JP-H 3 Hz, CH-4), 7.40 (3H, m, Ph), 8.00 (2H, m, Ph).