Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH:23]([SH:26])[CH2:24][CH3:25].O>C(#N)C>[CH3:22][CH:23]([S:26][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:24][CH3:25]
Reactant: CCC(C)S
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(C)Sc1cc(C(F)(F)F)ccc1C#N
Yield: 74.9 %

Procedure:
2-Nitro-4-trifluoromethylbenzonitrile (10.8 g) and potassium carbonate (8.3 g) were heated to reflux in acetonitrile. A solution of 1-methylpropanethiol (5 g) in acetonitrile was added. The resultant suspension was heated at reflux for 4.5 hours. After cooling water was added and the mixture extracted with ethyl acetate. The organic extracts were washed with water. The organic extracts were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography eluting with ethyl acetate in cyclohexane to give 2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzonitrile (9.7 g) as a yellow oil, NMR (CDCl3) 1.0(t,3H), 1.2(d,3H), 1.5(m,1H), 3.4(m,1H), 7.3(m,1H), 7.6(m,2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:24]2[CH2:28][S:27]C(=S)[S:25]2)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:24]([SH:25])[CH2:28][SH:27])[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(C2CSC(=S)S2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(S)CS)cc(OC)c1OC
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.20 g, 5.27 mmole) is added to 15 ml dry diethylether. To this slurry is added 4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione (32) (1.0 g, 3.31 mmole) predissolved in 20 ml dry THF. The reaction is refluxed under an N2 atmosphere for 12 hours. The reaction is cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture is acidified with 10% HCl and immediately extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, filtered and evaporated to a white solid (9.836 g, 97%). NMR: (DCDl3) 2.34,d,1H;2.95,m,1H;3.09,m,1H; 3.84,s,3H;3.87,s,6H;4.03,m,1H;6.53,s,2H. M.S. (IBu) 261 (100%). Melting Point: 72.5°-73.5° C. C,H,S Analysis: (theoretical, actual) C (50.74,50.85); H (6.19,6.20); S (24.63,24.53).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH:30]([CH3:32])[CH3:31]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=1[CH:30]([CH3:32])[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(S(C)(=O)=O)cc1I
Product: CC(C)c1ccc(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-1-isopropyl-4-(methylsulfonyl)benzene (Intermediate 91), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[Mg].Cl[C:13]([O:15][CH3:16])=[O:14]>C1COCC1>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:4]=1)([CH3:8])=[CH2:7]
Reactant: COC(=O)Cl
Reactant: C=C(C)c1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(C(=O)OC)cc1

Procedure:
Preparation of the Grignard compound of 4-chloro-α-methylstyrene by means of Rieke magnesium in THF under reflux and subsequent reaction with 0.95 equivalents of methyl chloroformate at RT. Aqueous working up, extraction with ethyl acetate and column chromatography using cyclohexane/ethyl acetate 85:15 affords methyl 4-isopropenylbenzoate as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2ncccc2c1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: c1ccc(-c2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Quinoline (40 g) was dissolved in dry ether (250 ml) and treated dropwise with a solution of phenyl lithium (160 ml of 1.88 m solution in benzene/ether). The mixture was stirred at room temperature for 18 hr., then washed with aqueous ammonium chloride solution (20% w/v 2×100 ml) and then water (2×100 ml). The aqueous phase was extracted with ether (2×100 ml) and the combined ether layers were dried (magnesium sulphate) and evaporated in vacuo to give an oil. Unreacted quinoline was removed from the product by distillation in vacuo (80°-90°/10-15 mm Hg). A portion of the residue was crystallised from industrial methylated spirit to afford 2-phenylquinoline m.pt. 84°-86° characterised by its nmr spectrum. The bulk of the product was also characterised by its nmr spectrum.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS(O[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[C:27]([O:34][C@@H:35]3[O:52][C@H:51]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]([O:42][C:43](=[O:45])[CH3:44])[C@H:36]3[O:37][C:38](=[O:40])[CH3:39])=[N:28][NH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])=[C:21]([CH3:58])[CH:20]=1)(=O)=O.[CH2:59]1[C:62]2([CH2:67][CH2:66][CH2:65][N:64]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:63]2)[CH2:61][NH:60]1>C(#N)C>[CH3:58][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[CH2:16][CH2:15][N:60]2[CH2:61][C:62]3([CH2:67][CH2:66][CH2:65][N:64]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:63]3)[CH2:59]2)[CH:24]=[CH:23][C:22]=1[CH2:25][C:26]1[C:27]([O:34][C@@H:35]2[O:52][C@H:51]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]([O:42][C:43](=[O:45])[CH3:44])[C@H:36]2[O:37][C:38](=[O:40])[CH3:39])=[N:28][NH:29][C:30]=1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC2(CNC2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CC4(CCCN(C(=O)OC(C)(C)C)C4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Yield: 53.6 %

Procedure:
Add diisopropylethylamine (0.2 mL, 1.1 mmol) to a solution of (3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl methanesulfonate (200 mg, 0.28 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (77 mg, 0.34 mmol) in acetonitrile (3 mL). Heat the mixture at 80° C. for overnight. Concentrate under reduced pressure and purify residue by flash chromatography to yield the title compound (127 mg, 0.15 mmol). MS (m/z): 838.8, 839.6 (M+1), 836.8, 837.6 (M−1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[CH:10]=[CH:9][C:5]3[N:6]=[CH:7][NH:8][C:4]=3[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CN)cc1
Reactant: Brc1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3nc[nH]c3c2)cc1

Procedure:
The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-methylbenzylamine (145 mg; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.058 g (24.5%); MS m/z: 238.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.24 (s, 3H); 4.21 (s, 2H); 5.97 (br s, 1H); 6.49 (s, 1H); 6.59 (dd, 1H, 4J=1.8 Hz, 3J=8.5 Hz); 7.08-7.10 (m, 2H); 7.24-7.26 (m, 3H); 7.82 (s, 1H); 11.82 (br s, 1H); HPLC (METHOD [A]): rt 11.87 min (96.2%)
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]2[N:18]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:19]=[CH:20][CH:21]=2)[CH:5]=1.[OH-].[Na+]>CO>[CH:23]1([CH2:22][N:18]2[C:17]([C:6]3[CH:5]=[C:4]([CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=4)[CH:7]=3)[C:3]([OH:26])=[O:2])=[CH:21][CH:20]=[N:19]2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2ccnn2CC2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3CC3CC3)c2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (1.14 g, 3.27 mmol was dissolved in 20 mL MeOH, and 3N aqueous NaOH (3 mL) was added. The reaction mixture was stirred at room temperature for three hours, then concentrated under reduced pressure. The residue was acidified to pH 3 and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 0.9 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid, MS (M+H)=334.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C[Si]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(C)C.[F-].[K+]>CN1CCCC1=O.[Cu](I)I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: Brc1ccc(I)cc1
Agent: I[Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A solution of 4-bromo-iodobenzene (500 mg, 1.77 mmol), trimethylsilylpentafluoroethane (679 mg, 3.53 mmol), copper iodide (672 mg, 3.53 mmol) and potassium fluoride (205 mg, 3.53 mmol) in N-methylpyrolidone (1.0 mL) was heated with stirring at 100° C. for three hours in a sealed reaction vessel. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 1-bromo-4-pentafluoroethylbenzene as a colorless liquid (253 mg, 52%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:10][C:11]=1[CH3:12])=[O:5])C.[OH-].[Na+]>C(O)C.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH3:12])[N:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCOCC2)nc(-c2ccccc2F)c1C(=O)O
Temperature: 25 °C
Yield: 12.4 %

Procedure:
A mixture of 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester (0.6 g, 10.96 mmol), and solid NaOH (2 g, 50 mmol) in ethanol (5 mL) and water (1 mL) was refluxed for 1 h, then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was acidified with a 6N HCl solution. Then, the product was extracted with EtOAC (3×25 mL) and the organic extracts were dried and concentrated to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (0.43 g, 78%) as white solid. Mass Spec. LCMS 318 (M+1).
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:22])C>>[CH3:13][C:2]1([CH3:14])[C:3](=[O:22])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[O:6]1
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccncc1
Solvent: CCNCC
Product: CC1(C)OC(c2ccncc2)=CC1=O
Reaction time: 0.67 h

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (1.49 g, 0.007 mol) in ethanol (15 mL), diethylamine (0.511 g, 0.007 mol) in EtOH (15 mL) was added dropwise at RT. The mixture was then stirred for additional 40 min. The EtOH was evaporated and the mixture was diluted with EtOAc (100 mL). The organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Cl[C:22]1[N:27]2[N:28]=[CH:29][CH:30]=[C:26]2[N:25]=[C:24]([CH3:31])[CH:23]=1.C(N(C(C)C)CC)(C)C.N1CCNCC1>C(OCC)(=O)C.C1COCC1>[CH3:31][C:24]1[CH:23]=[C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)[N:27]2[N:28]=[CH:29][CH:30]=[C:26]2[N:25]=1
Reactant: Cc1cc(Cl)n2nccc2n1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Agent: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)n2nccc2n1
Yield: 34.5 %

Procedure:
To a solution of THF (2 mL) containing 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.0 mmol) synthesized in Reference Example 61, 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (200 mg, 1.2 mmol) and diisopropylethylamine (0.42 mL) were added, and the mixture was heated to reflux for 2 hours. After addition of piperazine (42 mg, 0.50 mmol) thereto, the mixture was further heated to reflux for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried using magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 7:3). The obtained solid was recrystallized from ethanol-water to obtain 140 mg of the title compound (yield 35%). Melting point was 180 to 182° C. (ethanol-water).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:62][CH2:63][C:64]5[CH:65]=[CH:66][C:67]6[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=6[CH:75]=5)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)indolizine-8-carboxylic acid (10 mg, 0.023 mmol), HATU (13 mg, 0.035 mmol) and Et3N (0.02 mL, 0.11 mmol) in DMF (5 mL) was added 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (10 mg, 0.046 mmol). The mixture was stirred at rt overnight. EA (40 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)indolizine-8-carboxamide (4.8 mg; yield 34%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (t, J=6.0 Hz, 1H), 9.04 (s, 1H), 8.55 (s, 1H), 7.84 (s, 1H), 7.66-7.68 (m, 3H), 7.46 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.28-7.30 (m, 2H), 7.05-7.12 (m, 2H), 4.54-4.63 (m, 4H), 1.44 (s, 6H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=615.7 (M+1, ESI+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Br:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 23-(1) and 4-bromobenzoyl chloride were treated in a manner similar to Example 2-(4), (5) and 3-(3) to give 3-(4-bromophenylmethyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole as pale pink crystals. mp 190-192° C. APCI-Mass m/Z 630/632 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[CH:32][S:33][CH:34]=1)CCC.[Cl-].[Li+]>O1CCOCC1.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>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[N:31]=[CH:32][S:33][CH:34]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2cscn2)cc1
Yield: 68.7 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.318 g, 0.78 mmol, Example 35, step 3) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithium chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3.5 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.221 g, 68.8% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:35]N1C(C)(C)C(=O)N(Br)C1=O>ClC1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][Br:35])[N:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cccc(CBr)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 102.8 g (334 mmol) of t-butyl t-butoxycarbonyl-(6-methyl-pyridin-2-yl)-carbamate were added 10.95 g (20 mol %) of 2,2′-azobisisobutyronitrile and 1,330 ml of chlorobenzene. To the resulting mixture was added 95.31 g of 1,3-dibromo-5,5-dimethylhydantoin, and the temperature of the mixture was then raised to 90° C. at a rate of 2° C./minute and held at the temperature for one hour. Subsequently, the reaction mixture was cooled to 20° C., the precipitate was filtered off, and the volume of chlorobenzene was reduced by half by distillation. The thus obtained residue was cooled to 10° C. or lower, and then 46.03 g (43 ml) of diisopropylethylamine and 43.08 g (58 ml) of diethyl phosphite were added thereto, followed by aging the mixture at room temperature for 16.5 hours. Following confirmation by performing thin-layer chromatography that the raw materials had disappeared, the reaction mixture was washed with 300 ml of 3 N hydrochloric acid, and then further washed with 500 ml of a saturated saline solution. The resulting solution was then dried over anhydrous magnesium sulfate and filtered, yielding a solution of 2-bis(t-butoxycarbonyl)amino-6-bromomethyl-pyridine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([BH3-])#N.[Na+].[N:5](=[C:7]([CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[N:15]([CH3:24])[C:13]1=[O:14])[OH:6].Cl>CO.CCOCC>[OH:6][NH:5][CH:7]([CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[N:15]([CH3:24])[C:13]1=[O:14]
Reactant: CC(CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)=NO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)NO
Reaction time: 3 h

Procedure:
Sodium cyanoborohydride (62.84 mg, 1 mmol) was added to a solution of 1-(5-oximinohexyl)-3,7-dimethylxanthine (Klein, J. P.; Leigh, A. Oxime Substituted Therapeutic Compounds, U.S. Pat. No. 5,770,595 (Jun. 23, 1998)) (293 mg, 1 mmol) in methanol (10 ml). 1 M hydrogen chloride in ether was added to pH 4-5. After stirring for 3 hours, the mixture was concentrated under reduced pressure. 1 N aqueous sodium hydroxide solution to pH 9-10 (10 ml). The mixture was extracted with 10% methanol-dichloromethane (3×50 ml). The combined extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-dichloromethane to provide 1-(5-(N-hydroxy)aminohexyl)-3,7-dimethylxanthine (180 mg).