Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36]2[CH:45]=[C:44](O)[C:43]3[C:38](=[CH:39][C:40]([O:47][CH3:48])=[CH:41][CH:42]=3)[N:37]=2)[N:35]=1)([CH3:29])[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:24]([O:23][C:21]([C@@:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([O:13][C:44]3[C:43]4[C:38](=[CH:39][C:40]([O:47][CH3:48])=[CH:41][CH:42]=4)[N:37]=[C:36]([C:34]4[N:35]=[C:31]([NH:30][CH:27]([CH3:29])[CH3:28])[S:32][CH:33]=4)[CH:45]=3)[CH2:12][C@H:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:26])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:22])[CH3:25]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of compound 35 (0.10 mmol) in dry THF (4 mL) was added the quinoline 12 (0.16 mmol) and Ph3P (0.40 mmol). After cooling to 0° C. DIAD (0.40 mmol) was added dropwise during 5 min. The solution was stirred at 0° C. for 1 h and at rt for 48 h. The solvent was evaporated and the remainder was purified using flash column chromatography (toluene/EtOAc 1:1) to give the title compound (10%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a stirred solution of 4-bromo-1,2-difluorobenzene (3.5 g, 17.86 mmol) in dry THF was cooled to −78° C., was added a n-BuLi (10.71 mL) slution dropwise. After completion of the addition, the mixture was stirred for 15 min., and triisopropyl borate (6.71 g, 35.71 mmol) was added in one portion. The reaction flask was kept in a cooling bath for 30 min., and warmed to room temperature for 3 hours. The solvent was removed, the residue was dissolved in ether, washed with 1N HCl and water, dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by recrystallyzation with CH2Cl2 and hexane to give the pure 3,4-difluorophenylboronic acid (800 mg, 20%).
Reaction SMILES: [CH2:1]([C:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:13]=1)[CH:11]=O)=[CH:4][CH3:5])[CH3:2].[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][C:18]([C:19]1[S:20][C:9]2[CH:8]=[CH:7][C:6]([C:3]([CH2:1][CH3:2])=[CH:4][CH3:5])=[CH:13][C:10]=2[CH:11]=1)=[O:21])[CH3:16]
Reactant: CCOC(=O)CS
Reactant: CC=C(CC)c1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=C(CC)c1ccc2sc(C(=O)OCC)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 5-(1-ethyl-propenyl)-2-fluoro-benzaldehyde (8.70 g, 45.3 mmol) in DMF (40 mL) is treated with mercapto-acetic acid ethyl ester (8.16 g, 67.9 mmol) and K2CO3 (12.5 g, 90.6 mmol). The resulting suspension is stirred at 80° C. for 60 min and quenched with water (300 mL). The mixture is extracted with EtOAc (2×200 mL), and the organic layer is dried over Na2SO4, concentrated, and purified using silica gel column chromatography (6% EtOAc/Hex), to give the title compound as an oil (11.0 g, 89%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH2:15]I)[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC[O:20][C:21]([CH3:23])=[O:22].O>CC(O)=O.CC([O-])=O.[Ag+]>[C:21]([O:22][CH2:15][C@@H:13]1[CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C:11](=[O:17])[O:12]1)(=[O:20])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CI)C1
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 92.6 %

Procedure:
To a solution of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(iodomethyl)-tetrahydropyran-2-one (40.00 g, 108.0 mmol) in AcOH (660 mL), AgOAc (20.03 g, 118.8 mmol) is added. The resultant mixture is then heated at 125° C. for 6 hours. The reaction mixture is filtered through diatomite filter medium (Celite®). The obtained filtrate is evaporated to afford the residue. To this residue, EtOAc (500 mL) and water (600 mL) are added. The organic layer is separated and the aqueous layer is washed again with EtOAc (5×150 mL). The combined organic layers are washed with water (4×300 mL), brine (5×300 mL) and dried over anhydrous MgSO4, filtered and concentrated under the reduced pressure to afford 30.28 g (92.6%) of ((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)methyl acetate as yellow oil (HPLC purity 98%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20].[H-].[K+]>C1COCC1>[CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19]#[N:20]
Reactant: CC(C)(C)CO
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 2,2-dimethyl-1-propanol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 4-(2,2-dimethyl-propoxy)-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].[Cl-]>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1Cc2ccsc2Cc2ncccc21
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccsc3Cc3ncccc32)c(Cl)c1

Procedure:
As described for Reference Example 204 5-(2-chloro-4-nitrobenzoyl)-4,10-dihydro-5H-pyrido[3,2-b]thieno[2,3-e]azepine is reduced with stannus chloride (SnCl2) in ethanol to give the product as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[C:18]2([CH:23]=[CH:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[C:10]1=[O:42]>ClCCl>[CH3:8][CH:9]1[C:18]2([CH:19]=[CH:20][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:22][CH2:23]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:42]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)c2ncccc2C12C=CN(C(=O)OCc1ccccc1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)Nc2ncccc2C12C=CN(C(=O)OCc1ccccc1)CC2
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 mL, 53.8 mmol) was added to a solution of benzyl 3-methyl-2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate (0.10 g, 0.20 mmol) in dichloromethane (2 mL). After 2 h, the reaction mixture was concentrated. The concentrated mixture was diluted in dichloromethane (2 mL) and ethane-1,2-diamine (4 mL) was added. After 1 h, the reaction mixture was concentrated and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. MS 364.1 (M+1).
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].Cl[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39])=[O:33]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:32](=[O:33])([O:29][CH:15]1[CH2:14][CH:13]([OH:30])[C@H:12]([CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:4]([NH:3][CH2:2][CH3:1])=[O:5])[C@H:16]1/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39]
Reactant: O=C(Cl)OCCCCCl
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)CCC/C=C\C[C@H]1C(O)CC(OC(=O)OCCCCCl)[C@@H]1/C=C/[C@@H](O)CCc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of bimatoprost (Cayman Chemicals 16820, Lot 188757; 123 mg, 0.30 mmol) in DCM (3 mL) at 0° C. was added DMAP (39 mg, 0.31 mmol) followed by the slow addition of 4-chlorobutyl chloroformate (43 uL, 0.31 mmol). After 3 days at ambient temperature, the mixture was diluted with DCM and washed with water (1×) and brine (1×). The DCM layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture of regioisomers and diacylated products was submitted to column chromatography (ethyl acetate-hexane 25-100%, followed by methanol-dichloromethane (5-15%) to provide as the major component isolated, 11-acylated chloride g-1 (25 mg, 15%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 62.4 %

Procedure:
Ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (1.00 g, 3.27 mmol), PdCl2(PPh3)2 (115 mg, 0.16 mmol), CuI (44 mg, 0.23 mmol), and trimethylsilylacetylene (0.7 mL, 4.9 mmol) were dissolved in Et3N (5 mL). The mixture was immediately degassed by vacuum, and the flask was charged with N2. The mixture was heated overnight at 50° C. Water was added and then the solution was extracted with EtOAc (3×). The organic was washed with NH4Cl, brine and dried (MgSO4). The solvent was removed and then the residue was purified by silica gel column chromatography to obtain ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.66 g, 62% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 97.7 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 1l) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (83.6 mg, 98%).
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2[S:23][C:22]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[CH:21][C:20]=2[CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]2[S:23][C:22]([CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([O:14][CH2:13][C:9]3[NH:10][CH:11]=[CH:12][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:26])=[CH:21][C:20]=2[CH:31]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(C(=O)O)c1cc2cc(F)ccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2cc(F)ccc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzylpyrrolyl methanol (1.8 mmol), 2-(5-fluoro-2-benzothienyl)-3-methylbutanoic acid (2.0 mmol) and 4-dimethylaminopyridine (2.0 mmol) in 20 ml of methylene chloride and 2 ml of DMF is added N,N'-dicyclohexylcarbodiimide (2.0 mml). The reaction mixture is stirred, under nitrogen, for about two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous NaHCO3, water and saturated aqueous NaCl, dried over CaSO4 and solvent evaporated to yield 3-benzylpyrrolylmethyl 2-(5-fluoro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([C@H:8]([NH:38][C:39]([C@@H:41]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:9][C@H:10]([OH:37])[C@@H:11]([NH:19]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C>CN(C=O)C>[NH2:19][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:10]([OH:37])[CH2:9][C@@H:8]([NH:38][C:39]([C@@H:41]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 594.5 %

Procedure:
A solution of the product of Example 3C (0.130 g, 0.192 mmol) in DMF (6 mL) was treated with diethylamine (1.5 mL), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with ethyl acetate and ending with methanol to give the title compound (0.52 g, 60% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][S:36][CH2:37][CH2:38]O.CCOC(/N=N/C(OCC)=O)=O>O>[CH3:35][S:36][CH2:37][CH2:38][O:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1
Reactant: CSCCO
Reactant: CCCCCC(=O)Nc1ncc(O)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCCCCC(=O)Nc1ncc(OCCSC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
N-(5-Hydroxypyrimidin-2-yl)hexanamide (8.18 g, 39 mmol) and triphenylphosphine (20.5 g, 78 mmol) were mixed, and dried under reduced pressure, and then the atmosphere was substituted with argon. These substances were dissolved by heating in anhydrous N,N-dimethylformamide (80 mL), and the solution was cooled to room temperature, and then added with 2-methylthioethanol (5.4 g, 58.6 mmol). The reaction mixture was added with DEAD (2.2 M solution in toluene, 26.6 mL, 58.6 mmol) on an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with water (300 mL), and the mixture was stirred for 15 minutes, and then and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, the resulting residue was dissolved in saturated ammonia in methanol (60 mL), and the solution was left at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→hexane:acetone=2:1), and the concentrated residue was dissolved in chloroform by heating. The crystals obtained by ice cooling of the solution were removed, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain N-{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}hexanamide (6.8 g, 61%) as pale dark brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1)#[N:2].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=3)[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: N#Cc1ccc(B(O)O)cn1
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: COCCOC
Product: CC(C)n1nc(-c2ccc(C#N)nc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 12.8 %

Procedure:
A solution of 2-cyanopyridine 5-boronic acid pinocol ester (18 mg, 0.08 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA21 (2.5 mg, 14% yield). ESI-MS (M+H)+ m/z calcd 280.1, found 280.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[C:5]([O:14][CH3:15])=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([NH:20][NH:21][C:22](=[O:37])[CH:23]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)[CH2:24][CH2:25][CH2:26][Cl:27])=O>P(Cl)(Cl)(Cl)=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH:23]([C:22]1[O:37][C:18](/[CH:17]=[CH:16]/[C:3]2[CH:4]=[C:5]([O:14][CH3:15])[C:6]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[CH:7][C:2]=2[F:1])=[N:20][N:21]=1)[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2cc(F)c(F)c(F)c2)c(F)cc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3cc(F)c(F)c(F)c3)o2)c(F)cc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid N′-{(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (200 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for 5.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 180 mg of the title compound. The property value of the compound as follows.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH2:26]3)[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:46][C:47]([CH3:49])=[O:48]>O1CCCC1.C(O)(=O)C>[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH:26]3[C:47]([OH:48])([CH3:49])[CH3:46])[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Reactant: CC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3ccccc3)CC21
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a stirred solution of 60 μL of hexamethyl disilazane in 10 mL of dry tetrahydrofuran at 0° under argon was added dropwise 190 μL of butyllithium (1.37M in hexane). To this solution at -78° was added a solution of 106 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 1 mL of tetrahydrofuran over a 3 min period. The reaction mixture was stirred for 10 min after which time 25 μL of acetone was added. After 20 min, 50 μL of acetic acid was added, the reaction mixture was evaporated to a small volume, and partitioned between methylene chloride and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was subjected to preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with ether-petroleum ether (1:2) to afford 21 mg (17.4%) of solid 3 -phenylthio-6-(2-hydroxyprop-2-yl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester. IR (neat): 3400, 1765, 1685, 1545 cm-1 ; NMR (220 MHz; CDCl3): δ 1.17 (3H, s), 1.25 (1H, s), 1.32 (3H, s), 2.30 (1H, J=18, 3.5), 2.8-3.0 (2H, m), 3.11 (1H, dd, J=6, 3), 4.5 (1H, m), 6.93 (1H, s), and 7.2-7.6 (15H, m).
Reaction SMILES: FC1C=CC(C[N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=CC=1.[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1>CN(C)C=O>[N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[CH:40][C:31]=1[O:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:10]2[NH:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:24][CH2:23]1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nc(OCCN3CCC(Nc4nc5ccccc5[nH]4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.5 Parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol and 135 parts of N,N-dimethyl-formamide were stirred at room temperature and 0.75 parts of a sodium hydride dispersion 50% were added. After stirring for one hour at room temperature, 2.5 parts of 2-chloroquinoline were added and the whole was stirred overnight at room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 4.3 parts (58%) of 1-[(4-fluorophenyl)-methyl[-N-[1-[2-(2-quinolinyloxy)ethyl]- 4-piperidinyl]-1H-benzimidazol-2-amine; mp. 149.9° C. (compound 77)