Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5](O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([S:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Product: CCCCCCCN(CCc1ccc(CC(Sc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting benzenethiol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (51 mg, 87%).
Reaction SMILES: [CH2:1](O)[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4](O)[C@@H:3]1O.C1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C(C)O>C(O)C>[OH:20][CH:5]([CH:4]=[CH2:3])[C:6]([O:7][CH2:2][CH3:1])=[O:8]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCOC(=O)C(C)O
Solvent: c1ccc2ccccc2c1
Solvent: CCO
Product: C=CC(O)C(=O)OCC
Temperature: 160 °C
Yield: 48 %

Procedure:
An autoclave (50 cc microclave) is charged with 8.0 g of ethanol, 0.2252 g of sucrose (0.6578 mmol), 118.9 mg naphthalene (internal standard) and finally with 160.0 mg Sn-BEA (prepared according to U.S. Pat. No. 6,306,364). The autoclave is closed, charged with 20 bar of argon and heated to 160° C. After the temperature reaches 100° C., the mechanical stirrer is started (500 rpm) and the mixture is heated for 20 hours under these conditions. GC-analysis of the reaction mixture shows that 1.03 mmol of ethyl lactate is formed (39%) together with 0.316 mmol ethyl 2-hydroxy-3-butenoate (16%).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]C=2)[CH2:3][CH2:2]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CC[O:24][CH2:25][CH3:26]>CC(C)=O>[CH3:11][S:12]([O:10][C:1]1[CH:9]=[C:26]2[C:4]([CH2:5][CH:6]([CH3:7])[C:25]2=[O:24])=[CH:3][CH:2]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCC
Reactant: O=C1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1Cc2ccc(OS(C)(=O)=O)cc2C1=O

Procedure:
A mixture of the indanone above (5.0 gm.), methanesulfonyl chloride (3.7 gm.) and potassium carbonate (5.0 gm.) in acetone (50 ml.) is refluxed for 24 hrs. Ether (100 ml.) is added and the ether layer washed with water (2 × 50 ml.), dried (MgSO4), filtered and evaporated to dryness to give the 6-methanesulfonyloxy-2-methylindanone (5.0 gm.) as a yellow oil.
Reaction SMILES: [Na].[C:2]1([SH:8])C=CC=C[CH:3]=1.[CH2:9](OC(OCC)CBr)[CH3:10].Cl.O1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.O>[C:20]1([CH2:3][CH:2]=[S:8])[CH:10]=[CH:9][CH:23]=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: CCOC(CBr)OCC
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: S=CCc1ccccc1

Procedure:
23 g (1 mol) of sodium are dissolved in 400 ml of ethanol. After cooling, 110 g (1 mol) of thiophenol are added. 197 g (1 mol) of bromoacetaldehyde diethyl acetal are added dropwise to this mixture. The mixture is heated under reflux for 24 hours and cooled and the salt which has precipitated out is filtered off with suction. The filtrate is concentrated, water is added to the evaporation residue and the mixture is extracted 3 times with ether. The combined ether phases are washed with 1N sodium hydroxide solution and water, dried and concentrated. The evaporation residue obtained is dissolved in 1.2 l of tetrahydrofuran, 1 l of dilute hydrochloric acid is added and the mixture is heated under reflux for 3 hours. It is cooled, diluted with water and extracted 3 times with ether, and the combined ether phases are washed with water, sodium bicarbonate solution and water again, dried and concentrated. 150 g of crude oil are obtained, which is reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.CO[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:20]=1B(O)O.[C:30]([O-])([O-])=[O:31].[K+].[K+].C(COC)OC>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.O>[C:13]([C:4]1[CH:3]=[C:2]([C:20]2([O:31][CH3:30])[CH:19]=[CH:24][CH:23]=[C:22]([CH:25]=[O:26])[CH2:21]2)[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]=1[OH:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC1(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C=CC=C(C=O)C1
Yield: 61 %

Procedure:
The intermediate 3-(3,5-di-t-butyl-4-hydroxyphenyl)-3-methoxybenzaldehyde was prepared in a manner similar to the procedure described in Example 1 b using 4-bromo-2,6-di-t-butylphenol (0.50 g, 1.75 mmol), 2-methoxy-5-formylphenyl boronic acid (0.315 g, 1.75 mmol), tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.175 mmol), K2CO3 (0.95 g, 7.0 mmol), dimethoxyethane (15 mL) and H2O (1 mL); 367 mg, 61% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[CH2:15]1[C@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[CH2:17][NH:16]1.O.C(O)(C)C>C(N(CC)CC)C>[CH2:15]1[C@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[CH2:17][N:16]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: C1C[C@@H]2CNC[C@@H]2C1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(OCCCN2C[C@H]3CCC[C@H]3C2)cc1
Temperature: 20 °C
Yield: 83 %

Procedure:
15.2 kg of 4-(3-chloropropoxy)benzamide, 40.28 kg of cis-octahydrocyclopenta[c]pyrrole in 30% aqueous solution, 63.84 kg of water, 21.48 kg of isopropanol and 14.39 kg of triethylamine are introduced into a reactor. The reaction mixture is stirred and heated at reflux until all the starting material has been consumed. The reaction mixture is then cooled to 20° C., before being filtered and washed with a mixture of isopropanol and water. The product is obtained in the form of a powder in a yield of 83% and with a chemical purity of 97%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11].[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.[Li+].[OH-]>CN(C=O)C.C1COCC1.O>[C:14]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)/C=C/c1ccccc1O
Agent: [Li+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
To a solution of 8.2 g of (E)-3-(2-hydroxy-phenyl)-acrylic acid and 15.2 g of TBDMS-Cl in 10 ml of DMF was added 11.9 g of imidazole and the mixture was stirred at room temperature for 24 h. After aqueous work-up, the bis-silylated product was saponified with 2.1 g of LiOH in THF-H2O for 0.5 h at 0° C. The mixture was concentrated in vacuo and TBDMS-OH removed by extraction with hexane. The aqueous layer was acidified to pH 4 with KHSO4 and extracted with EtOAc. The organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. The semi-solid residue was suspended in hexane, filtered and the filtrate evaporated to dryness to yield 7.5 g of a pale yellow oil, which solidified upon standing.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18]Br)=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CC(C)OC(C)=O)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CC(C)OC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
18.0 g (51.4 mmol) of ethyl 6-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoate and 56.3 ml (205.6 mmol) of 90% triisopropyl phosphite are heated to 80° C. and and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2), giving ethyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate as an orange oil. yield.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[O:22][CH:23]=[CH:24][CH:25]=1.C(O)C1OC=CC=1>O.CS(C)=O>[CH2:20]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: OCc1ccco1
Product: O=C1c2ccccc2C(=O)N1OCc1ccco1
Reaction time: 18 h
Yield: 70 %

Procedure:
To a stirred mixture of N-hydroxyphthalimide (41 g.), anhydrous potassium carbonate (26.4 g.) and dry dimethyl sulphoxide (400 ml.) was added 2-chloromethylfuran (freshly prepared, but undistilled, from 46.2 g. furfuryl alcohol according to the method of W. R. Kirner JACS, 1928, 50, 1955). The mixture was stirred for 18 hr., then poured into water (1.51). The precipitated solid was filtered off, washed well with water, and recrystallised from ethanol to give N-furfuryloxyphthalimide (42.8 g., 70%), m.p. 145.3°-146.2° τ values (DMSO-d6) are 4.80 (CH2), 2.22, 3.30, 3.50 (furyl protons) 2.08 (phthalimide protons). (b) Furfuryloxamine Hydrochloride.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16](O)[CH3:17].CCOC(C)=O.[C:25]1([CH3:31])[CH:30]=C[CH:28]=[CH:27][CH:26]=1>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>[CH3:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:16]([CH3:17])[C:30]=1[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: COc1ccc(Cl)nn1
Reactant: Cc1ccccc1
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: CCOC(C)=O
Product: COc1ccc(-c2c(C)cccc2C)nn1
Temperature: 25 °C

Procedure:
A mixture of 3-chloro-6-methoxy-pyridazine (1.44 g, 10 mmol), 2,6-methyl-phenyl boronic acid (1.73 g, 11.5 mmol), sodium carbonate (2 M aqueous solution, 10.5 ml, 21 mmol), ethanol (2 ml) and Pd(PPh3)4 (232 mg, 0.2 mmol) is refluxed in toluene (60 ml) overnight and then cooled to room temperature. EtOAc (20 ml) is added to the mixture and the organic layer is separated. The organic layer is washed with water, dried, and solvent removed. The crude product is purified by flash silica gel column (Hexanes/EtOAc 4:1) to give 3-(2,6-dimethyl-phenyl)-6-methoxy-pyridazine. 1H NMR: (CDCl3) 7.21-7.30 (m, 2H), 7.12 (d, 2H), 7.03 (d, 2H), 4.20 (s, 3H), 2.05 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](O)=[O:20])=[N:11][C:12]3[N:13]([N:16]=[CH:17][CH:18]=3)[C:14]=2[F:15])=[C:4]([F:22])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:41]=[N:40]C=2C=1.NN.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:40][NH2:41])=[O:20])=[N:11][C:12]3[N:13]([N:16]=[CH:17][CH:18]=3)[C:14]=2[F:15])=[C:4]([F:22])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NNC(=O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
A mixture of 6-(4-bromo-2-fluorophenylamino)-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMF is stirred for 30 minutes. Hydrazine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After 3 hours, the reaction mixture is diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:34])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3.[OH-].[Na+]>O.Cl>[C:2]([NH:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:34])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3ccccc3C)n(CCN)c(=O)n1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3ccccc3C)n(CCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
Sodium cyanate (0.64 g, 9.8 mmol) in water (13 ml) was added dropwise to a stirred solution of amine 3 (2 g, 4.9 mmol) in water (63 ml) and 1M HCl (9.8 ml) at 80° C. After stirring for 3 h at 80° C. the mixture was cooled and basified with 2M NaOH. The mixture was extracted with CH2Cl2 until no more product remained in the organic phase. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography [dichloromethane/methanol (97:3)] and the product triturated with ether to afford the title compound (1.0 g, 45%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:18]=1.Cl.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (8.5 g) and 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (7.4 g) (intermediate XX) in dioxane (100 ml) was added HCl in dioxan (4M; 0.9 ml). The reaction was stirred at 100° C. overnight. The reaction mixture was allowed to warm to room temperature and water (50 ml) was added. The precipitate was isolated by filtration
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[SiH3][O:30][SiH3].[F-].C([N+](CC[CH2:48][CH3:49])(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH2:49][CH2:48][OH:30])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: [SiH3]O[SiH3]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [F-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(OCCO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (150.0 mg, 0.365 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (23.4 mg, 0.584 mmol) at 0° C. After 30 min, to the mixture was added (2-bromomethoxy)-tert-butyldimethylsilane (0.39 mL, 1.83 mmol). The reaction mixture was stirred at room temperature for 3 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. To a solution of silyl ether (76.3 mg, 0.134 mmol) in tetrahydrofuran (1.0 mL) was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.27 mL, 0.268 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hrs. The starting material wasn't consumed completely. To the mixture was added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.13 mL, 0.134 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (35.6 mg, 0.0783 mmol, 21% (2 steps)).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)[CH:8]1[CH2:32][C:33]3[C:38]([CH:7]21)=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[NH:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:72]([NH2:76])[CH:73]([CH3:75])[CH3:74]>CN(C=O)C>[CH2:72]([NH:76][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:15]2[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH:9]2[CH:8]3[CH2:32][C:33]4[C:38]([CH:7]3[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:3])[NH2:2])[CH:5]=3)[NH:10]2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=1)=[O:31])[CH:73]([CH3:75])[CH3:74]
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2)cc1O
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCC(C)C)cc2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(0.1 mmol; 50.5 mg) of 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-4′-methoxy-biphenyl-4-carboxylic acid was dissolved in 4 mL of DMF followed by the addition of HATU (0.3 mmol; 114 mg), N,N-diisoproplyethylamine (0.6 mmol; 0.1 mL) and isobutylamine (0.6 mmol; 0.6 ml). The reaction was stirred at room temperature for 18 hours, filtered and purified by LC/MS prep system to give 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-4′-methoxy-biphenyl-4-carboxylic acid isobutyl-amide. Mass spectrum: 561 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23](N5CCOCC5)=[O:24])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:3][CH2:2]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][CH:23]([OH:24])[CH3:32])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=C(COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1)N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-5-yl)oxy)-1-(morpholin-4-yl)ethanone (4.36 g) in THF (25 mL) was added methylmagnesium bromide (1 M THF solution, 15.2 mL), and the reaction mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in a mixed solvent of THF (10 mL)-methanol (10 mL) was added sodium tetrahydroborate (383 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.48 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:25][O:26][C:27]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:28]=1[NH2:29].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.C(#N)C>[CH3:25][O:26][C:27]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=23)[CH:31]=[CH:30][C:28]=1[NH2:29]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1N
Temperature: 89 °C

Procedure:
To a suspension of 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (0.714 mmol, 280 mg) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.714 mmol, 178 mg) in dioxane (5 mL) was added aqueous 2M potassium carbonate (3.57 mmol, 1.78 mL). The mixture was degassed and put under a nitrogen atmosphere. Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.050 mmol, 40.4 mg) was added and the reaction mixture was heated to 89° C. After three hours the reaction mixture was diluted with acetonitrile (9 ml) and filtered over decalite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/methanol 5/1) to give 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)aniline (115 mg).