Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:4]([OH:21])[C:5]#[C:6][C:7]([CH3:20])=[CH:8][CH:9]=[C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[O:18])[CH:12]=[C:11]1[CH3:19])=[CH2:3].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1C=CC=CC=1>[CH3:3][C:2]([CH:4]([OH:21])/[CH:5]=[CH:6]\[C:7]([CH3:20])=[CH:8][CH:9]=[C:10]1[C:15]([CH3:16])([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]=[C:11]1[CH3:19])=[CH2:1]
Reactant: C=C(C)C(O)C#CC(C)=CC=C1C(C)=CC(=O)CC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccccc1
Product: C=C(C)C(O)/C=C\C(C)=CC=C1C(C)=CC(=O)CC1(C)C

Procedure:
6.5 g. of purified 2,6-dimethyl-8-(4-oxo-2,6,6-trimethyl-2-cyclohexenylidene)-1,6-octadien-4-yn-3-ol was hydrogenated with 1 g. of Lindlar catalyst (a palladium-clacium carbonate catalyst deactivated by the addition of lead and quinoline) in benzene. 700 ml. of hydrogen was consumed within 4 hours. After this period, the catalyst was removed from the solution and the solution was washed with water, then dried and evaporated under reduced pressure. The product was purified by chromatography on 200 g. of silica gel G using petroleum ether and ethyl ether solvent in a volume ratio of 1 to 3. The material was identified as 4-cis-2,6-dimethyl-8-(4-oxo-2,6,6-trimethyl-2-cyclohexenylidene)-1,4,6-octatrien-3-ol).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[C:20]([C:19]1[CH:22]=[C:23]([CH3:24])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)#[N:21]
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)nc2)CC1
Yield: 80.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (200 mg) described in Preparation Example 131 and (R)-4-methyloxazolidin-2-one (79 mg) described in Preparation Example 25, the title compound (170 mg) was obtained.
Reaction SMILES: C[C@H]1O[C@H]2O[C@H]3[C@H](O[C@@]2(O)C(=[O:5])C1)[C@@H](NC)[C@@H](O)[C@@H](NC)[C@@H]3O.[CH:24]1[C:30]([F:31])=[C:29](N)[NH:28][C:26](=[O:27])[N:25]=1>>[CH:29]1[NH:28][C:26](=[O:27])[NH:25][C:24](=[O:5])[C:30]=1[F:31]
Reactant: Nc1[nH]c(=O)ncc1F
Reactant: CN[C@@H]1[C@H](O)[C@H](NC)[C@H]2O[C@@]3(O)C(=O)C[C@@H](C)O[C@H]3O[C@@H]2[C@H]1O
Product: O=c1[nH]cc(F)c(=O)[nH]1
Reaction time: 72 h

Procedure:
Bifidobacterium longum/pAV001-HU-eCD obtained in Reference Example 1 was inoculated into 5 mL of MRS medium containing the antibiotic spectinomycin and 50 μg/mL of 5-FC, followed by anaerobic culture at 37° C. for 72 hours. Then, 1 mL of the culture medium was similarly inoculated into 9 mL of MRS medium containing the antibiotic spectinomycin and 50 μg/mL of 5-FC, and cultured for 24 hours under the same culture conditions. This inoculation step was repeated three rounds to produce the 5-FU-resistant Bifidobacterium longum/pAV001-HU-eCD. Next, the 5-FU-resistant growth of the produced 5-FU-resistant Bifidobacterium longum/pAV001-HU-eCD was confirmed by inoculating into MRS medium containing 20 μg/mL of 5-FU and the antibiotic spectinomycin and culturing for 24 hours under the same culture conditions as above. Then, the bacteria were suspended with glycerol and stored at −80° C. as glycerol stocks. The stored bacteria sample and wild-type Bifidobacterium longum were inoculated respectively into MRS media containing 250 μg/mL of 5-FU and the antibiotic spectinomycin and growths thereof were compared. The growth of bacteria from the stored sample was observed on the following day, indicating the maintenance of 5-FU resistance, while the wild type did not grow. Viable cell counts of the post-culture bacterial culture were determined by plate count method. The viable cell count was 2 to 3×109 CFU/mL for the bacterial culture of the stored sample, while that of the wild type was below the limit of detection (below 103 CFU/mL).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C(OC(C)C)(C)C.CC(O)C>C(O)CCC>[CH3:23][N:19]1[CH2:18][CH:17]([CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:9][CH2:10]2)[O:21][C:20]1=[O:22]
Reactant: CN1CC(CCCl)OC1=O
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: Cc1ccccc1N1CCN(CCC2CN(C)C(=O)O2)CC1
Yield: 57.7 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.5 g (0.02 mol) of 1-(2-methylphenyl)piperazine (Emka-Chemie), 3.3 g (0.02 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 6.4 g (0.06 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.5 g (50%) of white solid, mp 55°-57° C. (isopropyl ether/2-propanol).
Reaction SMILES: [Li].[N:2]([N:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])=O.O1C2CCCCC12.C(N)(C)(C)C.N([O-])=O.[Na+].[ClH:32]>>[ClH:32].[C:12]([N:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])[NH2:2])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N(N=O)C1CCCCC1O
Agent: C1CCC2OC2C1
Agent: Cl
Agent: O=N[O-]
Solvent: CC(C)(C)N
Product: CC(C)(C)N(N)C1CCCCC1O
Temperature: 50 °C

Procedure:
10 g of lithium alanate are added in portions of 1 g to a solution of 38.8 g of N-nitroso-tert.-butyl-(2-hydroxycyclohexyl)amine (obtained by heating 1,2-epoxy-cyclohexane with tert.butylamine at 150° C. in an autoclave and then nitrosating the mixture with sodium nitrite/HCl) under a nitrogen atmosphere in the course of 2 days, the mixture being heated at 50° C. The residual lithium alanate is destroyed by cooling the mixture and careful dropwise addition of 50 ml of methanol and then 75 ml of water. The mixture is then filtered and the filtrate is concentrated. The residue is taken up in 100 ml of methylene chloride, the water which separates out is separated off and the organic phase is dried and concentrated again. The oil thus obtainable is dissolved in 20 ml of ethanol and 150 ml of tert.-butyl methyl ether, and the hydrazine hydrochloride is precipitated by addition of ethereal HCl. Yield: 28.5 g melting point: 145° C. (decomp.)
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C@@H:12]([OH:16])[C:13]([OH:15])=[O:14]>CCCCCC.CO.C1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C@@H:12]([OH:16])[C:13]([O:15][CH3:1])=[O:14]
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
18.3 g of a 10% w/v solution of trimethylsilyldiazomethane in hexane were added dropwise to a solution of 28 g of (R)-3-chloromandelic acid (prepared as described in Preparation 46) in a mixture of 300 ml of methanol and 700 ml of benzene, and the resulting mixture was stirred for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, to give the title compound having [α]D23 -119.3° (c=1.00, chloroform) and an Rf=0.36 (thin layer chromatography over silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane) as a crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]C)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:21][NH2:22]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:21][NH2:22])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 84 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].FC(F)(F)S(O[C:18]1[C:19]2[CH2:39][N:38]([C:40](=[O:42])[CH3:41])[CH2:37][CH2:36][C:20]=2[N:21]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:35][CH:34]=[N:33][CH:32]=3)=[CH:27][CH:26]=2)[N:23]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[OH:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:2]([CH3:1])[C:18]1[C:19]2[CH2:39][N:38]([C:40](=[O:42])[CH3:41])[CH2:37][CH2:36][C:20]=2[N:21]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:35][CH:34]=[N:33][CH:32]=3)=[CH:27][CH:26]=2)[N:23]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CNCc1ccccc1CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)Cc3ccccc3CO)c2C1
Yield: 15.3 %

Procedure:
1-(4-((2-(Hydroxymethyl)benzyl)(methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12.3 mg, 15.3%) was prepared from (2-((methylamino)methyl)phenyl)methanol and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-y1 trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:10]2[N:11](COC)[CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.C(OCN1C=CN=C1C(C1C=CC(Cl)=CC=1)(C1C=CC=CC=1)O)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: COCn1ccnc1C(O)(c1ccccc1)c1ccc(F)cc1
Agent: OC(c1ccccc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Product: OC(c1ccccc1)(c1ccc(F)cc1)c1ncc[nH]1

Procedure:
Using the procedure described in Example VIC but substituting an equivalent amount of α-(p-fluorophenyl)-1-(methoxymethyl)-α-phenylimidazole-2-methanol for the 1-[(benzyloxy)methyl]-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol, α-(p-fluorophenyl)-α-phenylimidazole-2-methanol was obtained. Its melting point was 199-200.5° C. after crystallisation from acetone.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=O)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COCC(C1CCN(C(OCC2C=CC=CC=2)=O)C1=O)NC1C=CC=CC=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@H:13]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5]1
Reactant: COCC(Nc1ccccc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: COCC(Nc1ccccc1)C1CCN(C(=O)OCc2ccccc2)C1=O
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)OCc1ccccc1

Procedure:
In the same manner as in Example 36 except that (2S,4S)-xylyl-skewphos was used as an asymmetric ligand instead of (2S,4S)-skewphos, benzyl 3-(2-methoxy-1-(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate was hydrogenated. Quantification by high performance liquid chromatography confirmed that the starting material, benzyl 3-(2-methoxy-1-(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate, remained by 11%, the reaction intermediate, benzyl 3-(2-methoxy-1-(phenylamino)ethyl)-2-oxopyrrolidine-1-carboxylate, remained by 32%, and the resultant product, (3aR,4R,9bR)-benzyl 4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate, was produced by 53%. The optical purity of the resultant product was 20% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[F:16][CH2:17]I.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:9][CH2:17][F:16])=[CH:5][N:6]=1
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: FCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FCOc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5,6-dichloro-pyridin-3-ol [11860-92-9] (500 mg, 3.05 mmol) and K2CO3 (632 mg, 4.57 mmol) in dry ACN (12 ml) was added fluoro-iodomethane (1.156 ml, 9.15 mmol) at 0° C. The light yellow suspension was stirred for 5 min at 0° C. and then heated up to 120° C. for 30 min. Saturated aq. NH4Cl was added, followed by EtOAc. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to give a brown oil. The crude material was directly used in the next step without further purification.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)([O-:3])=[O:2].[CH2:19]([NH2:21])[CH3:20]>>[N+:1]([CH:4]=[C:5]([NH:21][CH2:19][CH3:20])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1
Product: CCNC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene (see Example 85 (i)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]2([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:24]1[CH:23]=[C:22]2[C:17](=[CH:16][CH:15]=1)[C:18]([CH3:28])([CH3:27])[CH2:19][CH2:20][C:21]2([CH3:26])[CH3:25]
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1cccc(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of 2,6-dimethoxy-phenylboronic acid (1.0 g, 5.48 mmol), 6-bromo-1,1,4,4 tetramethy 1,2,3,4-tetrahydronaphthalene (0.73 g, 2.74 mmol) and potassium carbonate (1.50 g, 10.96 mmol) in 1,2-dimethoxyethane (20 mL) and water (1.0 mL) was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.60 g, 0.54 mmol) was added and the mixture heated at reflux under argon for 5 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.92 g of 6-(2,6-Dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH:18]=[CH2:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B(O)O)=[CH:36][C:30]=3[C:31]=2[C:32](=[O:35])[NH:33][CH3:34])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:8]([C:6]1[C:5]([CH:18]=[CH2:19])=[CH:4][N:3]=[C:2]([C:37]3[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]4[O:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)=[C:31]([C:32]([NH:33][CH3:34])=[O:35])[C:30]=4[CH:36]=3)[N:7]=1)[NH:9]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Reactant: C=Cc1cnc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cnc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 80 °C
Yield: 67.9 %

Procedure:
To a degassed solution of 2-(2-chloro-5-vinylpyrimidin-4-yl)-4-fluoro-1H-indole (100 mg, 0.36 mmol) and (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethyl sulfonamido)benzofuran-5-yl)boronic acid (150 mg, 0.36 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (20 mg), X-Phos (20 mg) and K3PO4 (200 mg, 0.56 mmol) were added under N2. The mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled to RT, filtered and washed with EtOAc. The filtrate was washed with H2O, brine, and dried over Na2SO4. After concentration, the residue was purified by column chromatography (DCM:MeOH 40:1) to give the product of 5-(4-(4-fluoro-1H-indol-2-yl)-5-vinylpyrimidin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 68.4%). 1H-NMR (CDCl3, 400 MHz) δ 10.76 (br s, 1H), 8.88 (s, 1H), 8.63 (s, 1H), 7.98˜8.05 (m, 2H), 7.64 (s, 1H), 7.59 (s, 1H), 7.15˜7.25 (m, 6H), 6.74˜6.84 (m, 1H), 5.91 (d, J=18.0 Hz, 1H), 5.69 (d, J=11.2 Hz, 1H), 3.39 (s, 3H), 3.03 (d, J=4.8 Hz, 3H), 2.87 (s, 3H). MS (M+H)+: 614
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.CC1(C)COB([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[N:32][CH:33]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[N:32][CH:33]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CC(C)COc1ccc(B2OCC(C)(C)CO2)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (1.00 g, 2.96 mmol) was mixed with 5,5-dimethyl-2-(2-isobutyloxypyridin-5-yl)-1,3,2-dioxaborinane (1.4 g, purity 80%, 4.3 mmol), Pd(PPh3)4 (0.17 g, 0.15 mmol) and sodium carbonate (0.62 g, 5.9 mmol) in tolune/ethanol/water 8:2:1 (15 ml) and refluxed for 8 hours under nitrogen. After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-isobutyloxypyridin-5-yl)phenyl]oxazoline was obtained, 1.14 g, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([OH:36])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH3:50]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH3:50])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol (0.054 g, 0.11 mmol) and potassium carbonate (0.059 g, 0.43 mmol) in DMF was added 1-bromo-2-(2-methoxyethoxy)ethane (0.057 ml, 0.43 mmol), the resulting mixture was stirred at 80° C. for 1 h. The crude product was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-60% (EtOAc-DCM) to afford 4-(4-chlorophenyl)-N-(4-(6-(2-(2-methoxyethoxy)ethoxy)quinolin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS: m/z=[M+H]+. 610.0 Calc'd for C34H29ClN4O3S: 609.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][CH:24]([CH2:28][CH2:29][Br:30])[C:25](Cl)=[O:26].O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:25](=[O:26])[CH:24]([Br:23])[CH2:28][CH2:29][Br:30])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C(Br)CCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)C(Br)CCBr
Reaction time: 0.25 h
Yield: 22.2 %

Procedure:
A solution of 12.8 g (64.2 mmol) 4-benzyloxyaniline and 9.74 g (96.3 mmol) triethylamine in 125 ml dichloromethane is cooled to 0° C. 20.4 g (77.1 mmol) of 2,4-dibromobutyryl chloride [Ikuta et al., J. Med. Chem. 30:1995 (1987)] is slowly added over a period of 45 min. The reaction mixture is stirred for additional 15 min, then hydrolysed with 100 ml of water. The insoluble precipitate is filtered off and the organic phase is washed successively with a saturated solution of sodium hydrogencarbonate and water. After drying and evaporation, the crude product is subjected to chromatography (silica gel, dichloromethane) to yield 6.1 g (22%) of a colorless solid. Mp=139.5–142° C.