Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:21][C:20](=[O:22])[C:19]([S:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:18]([OH:35])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:31]([C:25]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=1[S:23][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:11][CH:12]=2)([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][C:18]=1[OH:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)OC2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c1

Procedure:
Deprotection of 1.75 g (2.7 mmol) of 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl }-3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in the paragraph above) was accomplished as described in General Method 8 using 5.4 mL (5.4 mmol) of 1M tetrabutylammonium fluoride and 10 mL of THF. Purification by silica gel chromatography, eluting with MeOH:(50% Hexane-50% CH2Cl2) (1:99 to 5:95) gave the title compound, m.p. 154°-156° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]#[N:9])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:8]([CH2:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1)#[N:9]
Reactant: N#CCn1nnc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: N#CCn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 173-174° and MS: m/e=319.3 (M++H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2-yl)-acetonitrile and diphenylacetyl chloride.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].[C:15]([NH:22][C@H:23]([C:31](O)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:31](=[O:32])[C@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:22][C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A slurry of 36.4 g. L-histidine methyl ester dihydrochloride in dichloromethane (1 l.) was cooled to 5° C. and treated with 52 ml. triethylamine. After 10 minutes 40 g. Boc-L-phenylalanine was added followed by 1-hydroxybenzotriazole (30.6 g.), then after another 5 minutes by dicyclohexylcarbodiimide (30.8 g.), and the mixture was stirred at 0° C. for 4 hours and at 20° C. for 90 hours. The mixture was then filtered and the filtered solid was washed with dichloromethane, and the combined organic layers were concentrated and the residue was dissolved in 1 l. ethyl acetate. After 10 minutes of stirring the mixture was filtered and the filtrate was washed with 1N sodium hydroxide (3×150 ml.), brine, dried over magnesium sulfate and concentrated giving 45.9 g. of a colorless solid which was used without additional purification in Step B.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.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.C1(C)C=CC=CC=1>[C:13]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=3)[CH:3]=2)[CH:14]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Brc1ccc2cc(Br)ccc2c1
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: Cc1ccccc1
Product: Brc1ccc2cc(-c3cccc(-c4ccccc4)c3)ccc2c1
Yield: 51 %

Procedure:
Commercial 2,6-dibromonaphthalene in an amount of 12 g, 11 g of commercial 3-biphenylboronic acid and 180 ml of toluene were mixed together. Then, 5.7 g of tetrakis(triphenylphosphine)palladium and 90 ml of a 2 M aqueous solution of sodium carbonate were added, and the reaction system was purged with argon. After the reaction mixture was heated under the refluxing condition for 7.5 hours, the reaction mixture was cooled by leaving standing. The formed crystals were separated by filtration and subjected to extraction with toluene. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate, and the solvent was removed using an evaporator. The obtained residue was purified in accordance with the silica gel column chromatography (the developing solvent: hexane/toluene=5/1), and 7.8 g of 2-(biphenyl-3-yl)-6-bromonaphthalene was obtained as a white solid substance (the yield: 51%). 2-(Biphenyl-3-yl)-6-bromonaphthalene obtained above in an amount of 5.2 g, 6.4 g of 3-(9-phenylanthracen-10-yl)phenylboronic acid obtained in accordance with a conventional process, 60 ml of DME and 20 ml of toluene were mixed together. To the obtained solution, 0.67 g of tetrakis(triphenylphosphine)palladium and 60 ml of a 2 M aqueous solution of sodium carbonate were added, and the reaction system was purged with argon. After the reaction mixture was heated under the refluxing condition for 10 hours, the reaction mixture was cooled by leaving standing. The formed crystals were separated by filtration, washed with water and methanol and then with heated toluene, and 7.0 g of the object compound (AN-14) was obtained as a white solid substance (the yield: 74%). The obtained compound was examined in accordance with FD-MS (the field desorption mass analysis). Since it was found that m/z=658, which corresponded to C52H34=658, the obtained compound was identified to be AN-14.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: NCc1ccc(F)cc1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(NCc3ccc(F)cc3)c21
Temperature: 180 °C

Procedure:
A solution of 0.35 g (0.0015 mole) of 1-(2-butenyl)-7-choro-2,3-dimethylpyrrolo[2,3-d]pyridazine dissolved in 3.5 ml of 4-fluorobenzylamine was heated at 180° C. for 2.5 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and then poured into ice-water. The aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 30:1 mixture of chloroform and methanol as an eluent to give 0.22 g of 1-(2-butenyl)-7-(4-fluorobenzylamino)-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=1/4) as a flesh-colored powder.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[N:4]1)[CH3:2].[F:10][C:11]([F:22])([F:21])[C:12]1[N:17]=[CH:16][C:15]([CH2:18][C:19]#N)=[CH:14][CH:13]=1>CO.[Pd]>[CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][CH2:19][CH2:18][C:15]2[CH:16]=[N:17][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:13][CH:14]=2)[C:5]([CH3:9])=[N:4]1)[CH3:2]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: CCn1cc(N)c(C)n1
Agent: [Pd]
Solvent: CO
Product: CCn1cc(NCCc2ccc(C(F)(F)F)nc2)c(C)n1
Reaction time: 1.5 h
Yield: 13 %

Procedure:
A solution of 1-ethyl-3-methyl-1H-pyrazol-4-ylamine (1.345 g, 10.75 mmol, commercially available) and (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (distilled 166-175° C./2 mb, 1.0 g, 5.4 mmol) in MeOH (10 mL) was treated with HCO2NH4 (1.694 g, 26.86 mmol) and 10% Pd/C (200 mg) and stirred at 80° for 1.5 h. Filtration, concentration and purification by HPLC afforded the title compound (0.213 g, 13%) as a light brown oil. MS m/e: 299.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][NH:23][CH2:22]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][N:23]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:7])=[CH:4][CH:3]=1)[CH2:22]2
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Reactant: C1CC2CNCC(C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CC3CCCC(C3)C2)cc1

Procedure:
A solution of 4-fluoro-N-quinolin-3-yl-benzamide (0.080 g, 0.299 mmol), 3-aza-bicyclo[3.3.1]nonane (0.200 g, 1.60 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in dimethyl sulfoxide (2 mL) was heated to 100° C. for 11 days. The DMSO solution was applied to a preparative reverse phase C18 column, and the product was eluted with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, to give the product as a trifluoroacetate salt, a yellow solid, 0.065 g (36%). MS: m/z 372 (MH+). 1H NMR (DMSO-d6): 1.40-1.50 (m, 1 H), 1.58-1.93 (m, 7 H), 2.05 (br s, 2 H), 3.04-3.08 (m, 2 H), 3.85 (d, 2 H), 7.00 (d, 2 H), 7.62-7.76 (m, 2 H), 7.96 (d, 2 H), 8.02 (d, 2 H), 8.95 (d, 1 H), 9.28 (d, 1 H) and 10.45 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:7]=[N:8][C:9](=[O:12])[NH:10][CH:11]=1>CN(C)C=O.C(N(CC)CC)C>[CH3:1][NH:2][C:3]([N:10]1[CH:11]=[C:6]([Cl:5])[CH:7]=[N:8][C:9]1=[O:12])=[O:4]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Methyl isocyanate (56.5 ml) was added dropwise over 15 minutes, with cooling, to a stirred solution of 5-chloropyrimidin-2-one (25 g) in N,N-dimethylformamide (290 ml) and triethylamine (30.4 ml). The temperature of the reaction mixture was kept at approximately 22° C. The mixture was stirred at room temperature for a further 40 minutes and then cooled in an ice bath. The solid was collected, washed with cold dichloromethane (4×215 ml), briefly air dried and then dried in vacuo at room temperature to give the title compound as white crystals (33.36 g), m.p. 241°-243° C. decomp. U.V. data: λmaxEtOH 230 nm (ε10,370), 322.5 mm (ε1,700).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][C@H:9]1[CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)CC1COC(=O)C(C)(C)C
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)C[C@H]1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-(2,2-dimethyl-propionyloxymethyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared according to WO2007017828, 8.0 g, 26.7 mmol) and benzylamine (2.9 mL, 1 eq) in DCE (100 mL) were added NaBH(OAc)3 (7.9 g, 1.4 eq) and AcOH (1.53 mL, 1 eq) and the resulting solution was stirred at rt for 1 h. The mixture was quenched by adding NH4OH and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as a yellow oil (10.2 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([S:20](Cl)(=[O:22])=[O:21])([CH3:19])[CH3:18].N1C=CC=CC=1>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:20]([CH:17]([CH3:19])[CH3:18])(=[O:22])=[O:21])=[CH:3][C:4]=2[F:16])=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1F
Solvent: O
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)c(F)c1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
5-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (200 mg, 0.93 mmol) was dissolved in isopropyl sulfonyl chloride (0.50 mL, 2.8 mmol), pyridine (0.2 mL) was added and the mixture was heated to 100° C. for 6 hours. The mixture was then cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorophenyl]propane-2-sulfonamide (58 mg).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([N:19]3[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]3)=[CH:14][C:13]=2[CH3:27])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:37]OS(OC)(=O)=O.C(OCC)(=O)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([N:19]3[C:24](=[O:25])[N:23]([CH3:37])[C:22](=[O:26])[CH:21]=[N:20]3)=[CH:14][C:13]=2[CH3:27])=[O:7])=[CH:33][CH:34]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2C)cc1C(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)n(C)c3=O)cc2C)cc1C(=O)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-{4-[3-(4-fluoro-benzoyl)-4-methoxy-phenoxy]-3,5-dimethyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (50 mg) and potassium hydroxide (12 mg) in methanol (2 mL) was added dimethylsulfate (41 mg) to produce a thick slurry. After 3 h, the reaction mixture was diluted into ethyl acetate, washed with 1N aqueous sodium hydroxide, the organic layer dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was flash chromatographed on silica gel (20%-35% ethyl acetate/hexanes) to afford the title compound of this EXAMPLE as a colorless solid, 24 mg. MS Calc.:475.5 Found:476.2 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][C@@H:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Si:20]([O:21][C@@H:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[N:4][N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: N#Cc1cc(-c2nnc(Br)s2)ccc1F
Reactant: CC1(C)OB(c2cccc3c2CC[C@@H]3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 25 °C
Yield: 44 %

Procedure:
Prepared using General Procedure 1: A 20 mL microwave vial was charged with 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 (30 mg, 0.1 mmol), (S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-6 (43.6 mg, 0.11 mmol), potassium carbonate (44 mg, 0.32 mmol) and a 3:1 mixture of DME/H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 was added and mixture degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with EA (10 mL), and washed with water and brine. The organic layer dried over MgSO4, concentrated, and purified by silica gel chromatography (EA/hexanes) to provide 25 mg (44%) of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile as a light yellow solid. LCMS-ESI (m/z) calculated for C24H26FN3OSSi: 451.15; found 452.1 [M+H]+, tR=4.53 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.34-8.25 (m, 2H), 7.85 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.44-7.34 (m, 2H), 5.34 (t, J=7.1 Hz, 1H), 3.46 (ddd, J=16.8, 9.0, 2.8 Hz, 1H), 3.13 (dt, J=16.8, 8.3 Hz, 1H), 2.61-2.50 (m, 1H), 2.08-1.96 (m, 1H), 0.98-0.95 (m, 9H), 0.22-0.17 (m, 6H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH-].[Na+].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl>C1COCC1.O>[CH3:1][S:2]([NH:8][C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([OH:16])=[O:15])(=[O:4])=[O:3]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
A solution of methanesulfonyl chloride (0.593 mL, 7.62 mmol) in 1M NaOH (7.60 mL, 15.2 mmol) and THF (10 mL) was added drop wise to a stirred mixture of (L)-tert-leucine (1.0 g, 7.6 mmol), dissolved in THF (7.6 mL) and H2O (12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was acidified with 4M HCl and extracted with EtOAc. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give (2S)-2-methanesulphonylamino-3,3-dimethyl-butyric acid (0.486 g, 30%), which was analyzed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-methanesulfonylamino-3,3-dimethyl-butyric acid (0.476 g, 2.27 mmol), EDAC (0.481 g, 2.51 mmol), HOBT (0.338 g, 2.50 mmol), NMM (0.275 mL, 2.50 mmol), benzylhydrazine×2HCl (0.489 g, 2.51 mmol) and Et3N (0.700 mL, 4.98 mmol) which gave the title compound (0.416 g, 58%) as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[CH3:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Phenol (28.5 g, 0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous N,N-dimethylformamide (DMF) (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce 2-phenoxypropionic acid ethyl ester, shown above, as a golden oil (48.5 g, 83%) 1H NMR (250 MHz, CDCl3): δ 7.31 (d, 2H, J=7.8), 7.02 (t, 1H, J=7.9), 6.93 (d, 2H, J=7.8), 4.79 (q, 1H, J=6.1), 4.26 (q, 2H, J=7.2), 1.66 (d, 3H, J=6.1), 1.24 (t, 3H, J=7.2). MS [EI+] 195 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:43]=[CH:42][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:34][CH2:33][CH2:32][NH:31][C:29]([C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([O:17][C:16]3[CH:42]=[CH:43][C:13]([NH:12][C:10]([NH:9][C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])=[O:11])=[CH:14][CH:15]=3)[CH:23]=[CH:22][N:21]=2)[NH:28][CH:27]=1)=[O:30]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl (2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate (355 mg, 0.60 mmol) in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as brown solid. Yield: 260 mg, 88%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH2:15](Cl)[O:16]CCl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[C:11]([CH:15]=[O:16])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: ClCOCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C=O)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3.84 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 20 ml of dichloromethane, the whole is cooled to 0° and there are added dropwise thereto at from 0° to 5° firstly 3.16 g of titanium tetrachloride over a period of 3 minutes and then 3.83 g of dichlorodimethyl ether (Cl2CHOCH3) over a period of 20 minutes. The whole is then stirred for 5 minutes at from 0° to 5°, gradually heated to room temperature and then stirred for 15 minutes at 35°. The mixture is then left to cool to room temperature and poured onto 25 g of ice; the organic phase is separated off, the aqueous phase is then shaken three times with 10 ml of dichloromethane each time and the organic phases are combined, washed three times with 15 ml of ice-water each time, dried over magnesium sulphate, concentrated to dryness by evaporation and chromatographed over silica gel using dichloromethane as eluant. 4-formyl-5-methoxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of a colourless oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[NH:6]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([S:24](Cl)(=[O:26])=[O:25])=[C:15]2[O:20][C:21](=[O:23])[CH3:22])[C:7]([CH3:9])=[O:8]>CC(C)=O>[C:1]([NH:5][S:24]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[CH:19][C:10]=2[NH:6][C:7]([CH3:9])=[O:8])[C:15]=1[O:20][C:21](=[O:23])[CH3:22])(=[O:26])=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)NC(C)(C)C)ccc12
Reaction time: 8 h

Procedure:
14.5 g of t-butylamine in 50 ml of acetone were added dropwise to a solution of 18.8 g of the compound from stage 2 (0.55 mols) in 150 ml of acetone at -5° to 0° C. The mixture was further stirred overnight, filtered off from the deposit, concentrated and crystallized from ether with a little acetonitrile. Yield: 19.2 g=92% of the theoretical yield; mp: 203°-206° C.