Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:26][C:27]1[C:35]([CH:36]=[N:37][O:38][CH2:39][CH3:40])=[C:34]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].CC(C)(O)C#N.C(N(CC)CC)C>C(#N)C.O>[Cl:26][C:27]1[C:35]([CH:36]=[N:37][O:38][CH2:39][CH3:40])=[C:34]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:33]=[CH:32][C:28]=1[C:29]([CH:6]1[C:4](=[O:5])[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:9][C:7]1=[O:8])=[O:30]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CC(C)(C)CC2=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.26 g (0.009 mol) of dimedone and 1.90 g (0.009 mol) of dicyclohexylcarbodiimide were added to a solution of 2.95 g (0.009 mol) of 2-chloro-3-ethoxyiminomethyl-4-methylsulfonyl-benzoic acid in 130 ml of anhydrous acetonitrile. After stirring for 12 hours at room temperature, 0.42 g (0.005 mol) of acetone cyanohydrin and 3.27 g (0.032 mol) of triethylamine in 10 ml of absolute acetonitrile were added dropwise. The reaction mixture was then stirred for a further 2 hours at room temperature. With stirring, the reaction mixture was poured into 200 ml of water, the precipitate was filtered off with suction and the filtrate was added to 100 ml of 5% strength potassium carbonate solution. The aqueous phase was washed with ethyl acetate, the pH was adjusted to 2 using 10% strength hydrochloric acid and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water until neutral, dried and concentrated under reduced pressure. This gave 2.52 g of crude product which was recrystallized from toluene. (mp.: 156-157° C.)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=[N:16][N:17]=1.Cl.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])=[N:16][N:17]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2[N+](=O)[O-])o1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2N)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 2.8 %

Procedure:
To a suspension of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-5-(2-nitro-phenyl)-[1,3,4]oxadiazole (2.20 g, 63.2 mmol) in ethanol (100 mL) was added under a nitrogen atmosphere aqueous HCl (1 M, 7.6 mL, 76 mmol) and tin(II) chloride dihydrate (7.13 g, 31.6 mmol). The reaction mixture was then stirred for 2 h at 90° C., cooled to ambient temperature and poured onto an aqueous solution of sodium carbonate (saturated, 50 mL) and ethyl acetate (100 mL), stirred for 1 h and was filtered over Hyflo®. The Hyflo® was then washed with ethyl acetate (500 mL) and the aqueous phase extracted with ethyl acetate (100 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate 95:5 to 50:50) afforded the title compound (564 mg, 28%) as a white solid. MS: m/e=319.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27]CCCCC.CI>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: CCCCCC
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2coc3ccccc23)C1
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(C2=CCN(CCc3coc4ccccc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (342 mg, 1 mmol) (obtained from example 1, step 6) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Light green semi-solid. Yield: 280 mg (78%); 357 (M+H); 1H NMR: δ□7.94 (d, 1H), 7.6 9 (d, 1H), 7.5–7.0 (m, 8H), 6.2 (bs, 1H), 3.8 (s, 3H), 3.49 (bs, 2H), 3.0 (m, 2H), 2.85 (m, 4H), 2.6 (bs, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4]1.[OH-].[Na+].[C:13]([O:17][C:18](F)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl>O.O1CCOCC1.C(OCC)C>[C:18]([C:3]1([NH2:2])[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4]1)([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19]
Reactant: CC(C)(C)OC(=O)F
Reactant: NC1C=CC(C(=O)O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(N)C=CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
16.4 g of crude (±)-1-amino-2-cyclopentene-4-carboxylic acid hydrochloride (prepared as in J. Org. Chem. 1981, 46, 3268) were dissolved in a mixture of 80 ml of water and 80 ml of dioxane at room temperature under nitrogen. The mixture was then adjusted to pH 14 with 1N NaOH, and a diethyl ether solution of tert-butyloxycarbonyl fluoride (BOC-F, 20% excess) was 5 added (BOC-F prepared as in Synthesis 1975, 599). The mixture was stirred for a further 5 h at room temperature. The pH was adjusted to 2 with conc. HCl. After distillation of the organic solvents, 50 ml of water were added to the residue, and the mixture was extracted 3 times with 100 ml of ethyl acetate. The organic phase was evaporated to 50 ml and diluted with 25 ml of toluene. After cooling (0-10° C.), the title compound was filtered and dried. 14.3 g of product were obtained. The yield was 63%.
Reaction SMILES: [C:1]([O:9][CH2:10]C)(=[O:8])[CH2:2][C:3]([O:5][CH2:6]C)=[O:4].[H-].[Na+].Br[CH2:15][C:16]([CH3:18])=[CH2:17].[Cl-].[NH4+]>C1COCC1>[CH3:17][C:16](=[CH2:15])[CH2:18][CH:2]([C:1]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=C(C)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)C(=O)OC
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of diethyl malonate (2.30 g) in THF (20 mL) was added 60% sodium hydride (592 mg) at 0° C., and the mixture was stirred for 1 hr. 3Bromo-2-methylpropene (2.00 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.60 g) as a colorless oil.
Reaction SMILES: C([Li])CCC.[C:6]1([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:24]=[O:25])C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[C:6]1([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:14]=[C:13]2[CH:24]=[O:25])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-n2cnc3cnccc32)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2cnccc2n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
n-Butyl lithium (2.5M in hexanes, 6.8 mL, 17.1 mmol) was added to a solution of 1-phenyl-1H-imidazo[4,5-c]pyridine (1.85 g, 9.48 mmol) in THF (40 mL) at −78° C. under nitrogen. The mixture was kept at −78° C. for 15 minutes then at −10° C. for 10 minutes, and then re-cooled to −78° C. and DMF (1.5 mL, 0.190 mol) added. The reaction mixture was stirred at −78° C. for 15 minutes and −10° C. for 10 minutes. The mixture was poured into aqueous hydrochloric acid (1M, 80 mL) and the resultant mixture adjusted to pH 8 with saturated aqueous NaHCO3 (50 mL), then extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was in purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound as a yellow solid (0.72 g, 34%), containing methyl hemiacetal. LCMS (method H): Rt 1.28 min, [M+H]+ 224
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][N:29]1[C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:32]2[CH2:31][CH2:30][N:29]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH:28]([CH3:27])[CH2:33]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CC1CNCCN1c1ccc2ccccc2n1
Product: CC1CN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CCN1c1ccc2ccccc2n1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[2-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1
Reactant: CCOC(=O)c1csc(COCCOC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: COCCOCc1nc(CO)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of ethyl 2-((2-methoxyethoxy)methyl)thiazole-4-carboxylate (Example 6C, 2.27 g, 9.25 mmol) in ether (50 mL) was added portion wise lithium aluminum hydride (1.06 g, 27.9 mmol) over 10 min. at −78° C. The reaction was then stirred at −78° C. for 1 hour. Ethyl acetate (10 mL) was then added to the reaction followed by water (20 mL) and the reaction was allowed to reach RT. The mixture was then diluted with ethyl acetate, washed with HCl 1N (1×) and brine (1×). The combined aqueous phases were extracted with ethyl acetate (2×300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3.5×10 cm, ethyl acetate) to give the title material (0.357 g, 19%) as a brown oil. LC (Method F): 1.791 min. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.16 (s, 1H), 4.82 (s, 2H), 4.74 (broad s, 2H), 3.7-3.75 (m, 2H), 3.54-3.61 (m, 2H), 3.38 (s, 3H), 2.28 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[N:18]([CH3:23])[C:17]3[CH2:24][CH:25]4[NH:29][CH:28]([C:16]=3[C:15]=2[C:14]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[C:20]([CH3:22])[C:19]3[N:18]([CH3:23])[C:17]4[CH2:24][CH:25]5[NH:29][CH:28]([C:16]=4[C:15]=3[C:14]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Reactant: O=S([O-])c1cccc(Cl)c1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2cccc(Cl)c2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Yield: 39 %

Procedure:
Intermediate 1 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-chlorophenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (136 mg, 39%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.02 (s, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.83 (dt, J=7.5, 1.5 Hz, 1H), 7.43-7.49 (m, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.33 (s, 1H), 5.22 (br s, 1H), 4.71 (br s, 1H), 3.85 (s, 3H), 3.35 (br s, 1H), 2.76 (s, 3H), 2.45 (d, J=15.9 Hz, 1H), 2.12-2.38 (m, 2H), 1.86-1.97 (m, 1H), 1.52-1.66 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: C([O:5][C:6](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[CH2:7][C@H:8]([NH:11][C:12](=[O:33])[C@H:13]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:14][C:15](=[O:28])[CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH:9]=[O:10])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]1([O:17][CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[OH:5])=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(O)=NNC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.8 %

Procedure:
To a solution of (3S)-3-[N-((1-naphthyloxy)acetyl)leucinyl]amino-4-oxobutanoic acid tert-butyl ester semicarbazone (0.366 g 0.69 mmol) in CH2Cl2(2.0 mL)-anisole(0.5 mL) at room temperature under nitrogen was added trifluoroacetic acid (2.0 mL). The resulting solution was stirred at room temperature for 3 hrs, evaporated to dryness and chased with toluene-CH2Cl2 (1:1). The residue was triturated with Et2O to give the title compound (0.354 g, 100%) as an off-white solid. TLC(AcOH-MeOH-CH2Cl2; 1:1:20) Rf=0.25. TLC(EtOAc-pyridine-AcOH-H2O; 60:20:5:10) Rf=0.48.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([CH3:16])[CH:15]=1)=[O:10])[CH3:7].[OH-].[Na+].CN(C)[CH:21]=[O:22]>O>[CH2:6]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:21]=[O:22])=[C:14]([CH3:16])[CH:15]=1)=[O:10])[CH3:7]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(C)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(C)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To the ice-cold 3 mL (39.2 mmol) of dimethylformamide (DMF) was added phosphorus oxychloride (0.67 mL, 7.18 mmol) drop wise and the resultant mixture was stirred for 30 minutes. A solution of 1 g (6.53 mmol) of 4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester in 3 mL of DMF was added to the reaction. After 1 h, the reaction was warmed to room temperature for another 2.5 h. The reaction mixture was diluted with water (100 mL) and basified to pH=11 with 1N sodium hydroxide solution. The precipitate was removed by filtration, rinsing with water and dried to afford 0.8 g (68%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: COC(=O)C(=O)Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)C(=O)OC)cc1

Procedure:
A mixture of 0.10 mole of methyl p-aminophenylpyruvate, 0.10 mole of 1-bromohexadecane, and 0.10 mole of anhydrous potassium carbonate in 40 ml. of hexamethylphosphoramide is heated at 80° C. for 20 hrs. The mixture is then cooled, diluted with water and extracted with ether. The ethereal solution is then evaporated, yielding methyl (4-hexadecylaminophenyl)pyruvate.
Reaction SMILES: [CH2:1]([CH:3]([CH2:49][CH2:50][CH2:51][CH3:52])[C:4]#[C:5][C:6]1[C:24]2[S:25][C:26]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:27][C:23]=2[C:22]([C:38]#[C:39][CH:40]([CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH2:44]CC)=[C:8]2[S:9][C:10]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[CH:11][C:7]=12)[CH3:2]>[Pd]>[CH2:47]([CH:40]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH2:38][C:22]1[C:8]2[S:9][C:10]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:20])[CH3:21])[CH:13]([CH3:15])[CH3:14])=[CH:11][C:7]=2[C:6]([CH2:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:49][CH2:50][CH2:51][CH3:52])=[C:24]2[S:25][C:26]([Si:28]([CH:35]([CH3:36])[CH3:37])([CH:32]([CH3:33])[CH3:34])[CH:29]([CH3:30])[CH3:31])=[CH:27][C:23]=12)[CH3:48]
Reactant: CCCCCCC(C#Cc1c2cc([Si](C(C)C)(C(C)C)C(C)C)sc2c(C#CC(CC)CCCC)c2cc([Si](C(C)C)(C(C)C)C(C)C)sc12)CC
Agent: [Pd]
Product: CCCCC(CC)CCc1c2cc([Si](C(C)C)(C(C)C)C(C)C)sc2c(CCC(CC)CCCC)c2cc([Si](C(C)C)(C(C)C)C(C)C)sc12
Temperature: 95 °C
Yield: 97.1 %

Procedure:
A dry 100 mL three-neck round bottom flask equipped with a condenser was flushed with N2 and was charged with (4-(3-ethylhept-1-yn-1-yl)-8-(3-ethylnon-1-yn-1-yl)benzo[1,2-b:4,5-b′]dithiophene-2,6-diyl)bis(triisopropylsilane) (2.5 g, 3.3 mmol), Pd/C dry support (0.70 g, 10%) and anhydrous 1,4-dioxane (30 mL, 0.11 M). The flask was evacuated and backfilled with hydrogen. The reaction was kept under a hydrogen atmosphere and slowly heated to 95° C. Completion of hydrogenation was monitored by TLC. After hydrogenation was complete, the mixture was cooled to ambient temperature, filtered through Celite, and solvent was removed by rotary evaporation. The solid was dissolved in chloroform and precipitated into methanol to yield white solid (2.42 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][CH:25]([NH:33][C:34]([C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42](Br)[N:43]=2)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CN(C=O)C>CCOCC.[Cu]I.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>[CH3:24][CH:25]([NH:33][C:34]([C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:43]=2)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Reactant: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 60.8 %

Procedure:
6-Fluoro-3-tributylstannyl-1H-indazole (0.20 g, 0.47 mmol), copper(I) iodide (12 mg, 0.06 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide (200 mg, 0.41 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with nitrogen for 10 min then tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) was added. The reaction was stirred at 90° C. under nitrogen for 15 h. The reaction mixture was cooled, diluted with ether (60 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% methanol in dichloromethane with 0.5% ammonium hydroxide) to give 136 mg (61%) of 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=546.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:21]O>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH3:21])=[O:15])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1-c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1-c1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 5-bromo-[1,1′-biphenyl]-2-carboxylic acid (5 g, 18.2 mmol) in MeOH (30 mL) was added SOCl2 (10 mL) dropwise. The reaction mixture was heated to 70° C. for 2 h, then cooled to RT. The mixture was concentrated, adjusted to pH=7-8 with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/PE 50:1) to afford methyl 5-bromo-[1,1′-biphenyl]-2-carboxylate as a colorless oil.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2]>C(#N)C>[C:1]([S:5][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S
Solvent: CC#N
Product: CC(C)(C)SSC(C)(C)C

Procedure:
A 150 μg portion of LL-E33288γ1 -I in 1 ml of acetonitrile was treated with 50 μl of a 1μ mole/ml solution of t-butyl mercaptan in acetonitrile. After 21/4 hours, the reaction was complete, giving the t-butyl disulfide of LL-E33288γ1 -I.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>COCCOC.O1CCCC1.O>[CH2:1]([O:5][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][C:3]#[CH:4]
Reactant: Clc1ncccn1
Reactant: C#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: COCCOC
Product: C#CCCOc1ncccn1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of but-3-yn-1-ol (4.59 g, 65.5 mmol) in 1,2-dimethoxyethane (120 mL) was added 60% sodium hydride (2.45 g, 61.1 mmol) under ice-cooling, and the mixture was stirred for 1 hr. A solution of 2-chloropyrimidine (5.00 g, 43.7 mmol) in tetrahydrofuran (30 mL) was added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→60/40) to give the title compound (5.18 g, yield 80%).
Reaction SMILES: [CH3:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][O:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCOCC1(C)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)O)COCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-4-[(2-methylpropan-2-yl)oxycarbonyl]morpholine-3-carboxylic acid (Accela ChemBio Co., Ltd., CAS: 1052680-53-1, 50 mg, 0.2.0 mmol) in DCM (1 ml) was added trifluoroacetic acid (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for one hour and then concentrated under the vacuum. The residue was used directly in next step without further purification,