Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][CH:19]=[C:18]3[C:22]#[N:23])=[CH:13][CH:12]=2)[C:8]2[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[CH:20][CH:19]=[C:18]3[C:22]3[NH:38][N:37]=[N:36][N:23]=3)=[CH:15][CH:16]=2)[C:8]2[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-n2cccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-n2cccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
A solution of methyl 2-butyl-1-[[4-(2-cyano-1-pyrrolyl)phenyl]methyl]benzimidazole-7-carboxylate (2.2 g) and trimethyltin azide (3.3 g) in toluene (35 ml) was heated under reflux for 3 days. After concentration, the residue was dissolved in methanol (40 ml) and 1N hydrochloric acid (20 ml) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give crystals which were recrystallized from ethyl acetate to afford colorless crystals (1.8 g, 75%), m.p. 186°-187° C.
Reaction SMILES: Cl[C:2]1[CH:7]=CC=C(F)[C:3]=1[C:9]1[C:13](C#N)=[C:12](/C(/C(=O)C(F)(F)F)=C/N(C)C)[O:11][N:10]=1.ClC1C=C([NH:34][NH2:35])C=CC=1.CCN(C(C)C)C(C)C>C(O)C>[NH:34]1[CH:7]=[CH:2][C:3]([C:9]2[CH:13]=[CH:12][O:11][N:10]=2)=[N:35]1
Reactant: CN(C)/C=C(\C(=O)C(F)(F)F)c1onc(-c2c(F)cccc2Cl)c1C#N
Reactant: NNc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1cc(-c2ccon2)n[nH]1
Yield: 10.6 %

Procedure:
To a solution of 0.1 g (0.2579 mmol) (Z)-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carbonitrile in dry ethanol, 0.0462 g (0.2579 mmol) 3-Chlorophenylhydrazine and 0.78 mL (0.2579 mmol) DIPEA were added. The reaction mixture was heated under reflux for 3 h. The mixture was concentrated in vacuo and was dried in high vacuum. Purification was achieved by using pTLC, and 0.0037 g (yield of theory: 3.0%) of the pyrazolyl-isoxazole derivativewere obtained. Result of LC/MS MH+: 466.9; 1H NMR (DMSO-d6; CCl4): 7.73-7.97 (6H, m, CH-arom.), 8.04 (1H, s, CH-arom.), 8.81 (1H, s, CH-pyraz.)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:30])[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C1COCC1>[CH3:10][N:11]([CH3:30])[C:12]([CH:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:18][CH2:19]1)=[O:13]
Reactant: C=CC(=O)Cl
Reactant: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(C(=O)N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
Diisopropylethylamine (0.1 ml, 0.7 mmol) was added in one portion to a stirred solution of 1-(4-amino-benzenesulfonyl)-piperidine-4-carboxylic acid dimethylamide (0.15 g, 0.49 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.05 ml, 0.58 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (0.03 g, 15% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[K+]>COCCOCCOC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(CCC(F)(F)F)c1cccc(Br)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)(F)CCCc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-4,4,4-trifluoro-butan-1-one (3.1 g, 11 mmol) and diglyme was treated with hydrazine mono hydrate (5.5 g, 110.3 mmol), and stirred at 100° C. for 2 hours then treated with powder KOH (3.1 g, 55.1 mmol). The stirring continued at 150° C. for 6 hours. The mixture was cooled to room temperature, poured into a mixture of ice/water and extracted with ethyl ether. The extracts were combined, dried over MgSO4 and concentrated in vacuo. The crude product was purified on silica gel (ISCO) using hexanes as the eluting solvent to give 1-Bromo-3-(4,4,4-trifluoro-butyl)-benzene as a colorless oil (2.4 g, 88% yield). m/e (M)+ 266; 1H NMR (400 MHz, DMSO-d6) δ ppm, 1.7-1.8 (m, 2H), 2.1-2.2 (m, 2H), 2.6 (t, J=7.6 Hz, 2H), 7.2-7.25 (m, 2H), 7.3-7.35 (m, 1H), 7.4 (s, 1H)
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([OH:10])=[O:9])=[O:4].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([O:10][CH3:19])=[O:9])=[O:4]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(C(=O)CBr)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound obtained in Step B (27.4 mmol) is dissolved in 150 ml of MeOH, and 54.8 mmol of thionyl chloride are added dropwise in the cold state. The mixture is then stirred for 1 hour at ambient temperature and then for 2 hours at reflux. After evaporating off the methanol and the thionyl chloride, the oily residue is taken up in AcOEt, washed with water and then dried over MgSO4. The solvent is evaporated off under reduced pressure and the solid obtained is recrystallised.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][C:43]1[CH:44]=[C:45]([CH:50]2[CH2:55][NH:54][CH2:53][CH:52]([NH:56][C:57](=[O:64])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:51]2)[CH:46]=[CH:47][C:48]=1[CH3:49]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:42][C:43]1[CH:44]=[C:45]([CH:50]2[CH2:51][CH:52]([NH:56][C:57]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[O:64])[CH2:53][N:54]([C:15]([C:9]3([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[O:17])[CH2:55]2)[CH:46]=[CH:47][C:48]=1[CH3:49]
Reactant: Cc1ccc(C2CNCC(NC(=O)c3ccccc3)C2)cc1C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.3 mmol) of 4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-carboxylic acid together with 110 mg (0.3 mmol) of HATU and 47 mg (0.4 mmol) of 4-dimethylaminopyridine were initially charged in 2 ml of DMF, and 60 mg (0.2 mmol) of N-[5-(3,4-dimethylphenyl)piperidin-3-yl]benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 46 mg (44% of theory)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH:19]([F:21])[F:20])=[CH:13][CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(C)(C)C.Cl>ClCCl>[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:18][CH:19]([F:21])[F:20])[CH:11]=3)[CH2:16][CH2:17][CH:8]2[NH2:7])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(OC(F)F)cc2C1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: NC1CCc2ccc(OC(F)F)cc2C1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl[1-(4-chlorobenzyl)-7-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (30 mg, 0.069 mmol) was dissolved in dichloromethane (2 mL). 5N isopropanolic hydrochloric acid (0.3 mL) were added and the reaction mixture was stirred at room temperature for 3 h. The solvents were evaporated in vacuo. Yield: 26 mg (0.069 mmol, 100%, colorless solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](O)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][C:26]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:29]3[CH2:30][CH2:31][C:26]([OH:32])([CH3:25])[CH2:27][CH2:28]3)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(O)CCNCC1
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC(C)(O)CC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 51 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and 4-methyl-piperidin-4-ol gave the titled compound in 51% yield as off-white solid. MS: 471.2 (MH+, 2Cl).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([NH:22]C(=O)OC(C)(C)C)[CH:20]=5)[NH:15][C:14]4=[O:30])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:30])[C:13]12[CH2:12][CH:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:43][CH:42]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1(CC1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C5CC56C(=O)Nc5ccc(N)cc56)ccc34)cc2)CC1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
The Suzuki coupling was executed according to the method in Example A45, except substituting tert-butyl 2-(3-iodo-1H-indazol-6-yl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-ylcarbamate (70 mg, 0.136 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (57 mg, 0.190 mmol). The resulting product was dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. After 1 h the reaction was complete, the solvent was removed and the residue purified by prep-HPLC to give a white powder (3.2 mg, 15%); 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.53 (s, 1 H), 7.18 (d, J=8.8 Hz, 2H), 7.05-7.02 (m, 3H), 6.04 (s, 1H), 4.01-3.97 (bs, 2H), 3.75-3.65 (bs, 2H), 3.46 (t, J=8.4 Hz, 1H), 3.32-3.28 (bs, 2H), 3.18-3.08 (bs, 2H), 3.00 (s, 3H), 2.35-2.31 (m, 1H), 2.29-2.25 (m, 1H); MS ESI [M+H]+ 465.1, calcd for [C28H28N6O+H]+ 465.24.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(O)c1
Reactant: N#Cc1ccc(Br)cc1
Product: CC(C)c1cccc(Oc2ccc(C#N)cc2)c1
Yield: 33 %

Procedure:
Use a method similar to Preparation 32 (Step 1), using 4-bromobenzonitrile (2.0 g, 11.3 mmol) and 3-isopropylphenol (3.08 g, 22.6 mmol) to give 4-(3′-isopropylphenoxy)-benzonitrile (885 mg, 33%). MS (ES+) m/z: 255 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH:12]=O)([CH3:11])[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH2:12][NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)([CH3:11])[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Reactant: NCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(CCC(C)C)CNCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A solution of 2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (126 mg, 0.629 mmol) in ethanol (3 mL) was treated with 4-fluorobenzylamine (87 mg, 0.692 mmol) and stirred at 60° C. for 18 h. The reaction mixture was allowed to cool to 25° C. and treated with glacial acetic acid (0.036 mL, 0.629 mmol) followed by sodium cyanoborohydride (48 mg, 1.26 mmol). The reaction was stirred for 1 h at 25° C., quenched with a 1.0 M aqueous sodium hydroxide solution (2 mL), extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography (ISCO RediSep column, 0 to 40% ethyl acetate in hexanes) to give 2-[(4-fluoro-benzylamino)-methyl]-2,5-dimethyl-hexanoic acid ethyl ester (96 mg, 49%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.87 (d, 6H, J=6.0 Hz), 1.00-1.14 (m, 2H), 1.17 (s, 3H), 1.24 (t, 3H, J=7.0 Hz), 1.40-1.49 (m, 3H), 1.60 (sextet, 1H, J=6.1 Hz), 2.65 (dd, 2H, J1=108.4 Hz, J2=11.7, Hz), 3.74 (s, 2H), 4.12 (q, 2H, J=7.1 Hz), 6.98 (t, 2H, J=8.6 Hz), 7.26 (q, 2H, J=4.7 Hz). LC-MS (ESI) calculated for C18H28FNO2: 309.4, found 310.3 [M+H+].
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:10][C:9]2=[N:11][C:12]([CH2:14][CH3:15])=[CH:13][C:8]2=[C:7]([Cl:16])[N:6]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O1CCCC1.C(Cl)Cl>[CH3:3][S:4][C:5]1[N:6]=[C:7]([Cl:16])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=3)[C:9]=2[N:10]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
To a suspension of 48 mg (2.00 mmol) of sodium hydride in 4.0 mL of tetrahydrofuran was added 227 mg (1.00 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine and 478 mg (2.00 mmol) of 3-(trifluoromethyl)benzyl bromide. The reaction was stirred at ambient temperature for 18 hours then diluted with 30 mL of methylene chloride and washed with 20 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (25 g silica, methylene chloride-heptane gradient 1:1 to 100:0) to provide 320 mg (83%) of 2-(methylthio)-4-chloro-6-ethyl-7-[[3-(trifluoromethyl)-phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.31 (t, J=7.3 Hz, 3H), 2.58 (s, 3H), 2.59 (q, J=7.3 Hz, 2H), 5.44 (s, 2H), 6.31 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.54 (d, J=7.8 Hz, 1H)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[Cl:13].O.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:16]([NH:2][CH2:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)Cc1cc(Br)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CNC(=O)c1ccccc1)Cc1cc(Br)ccc1Cl
Reaction time: 3 h

Procedure:
A mixed solution of the above 1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene.hydrochloride (1.70 g) in ethyl acetate (30 ml)-water (15 ml) was cooled to 0° C. Added thereto were benzoyl chloride (0.99 ml) and sodium hydrogen carbonate (2.39 g), and the mixture was stirred at the same temperature for 3 hours. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=95:5) to give 1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) as a colorless solid. APCI-Mass m/Z 366/368 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][SH:8])[C:3]([NH2:5])=[S:4].[Na].Cl.Cl[CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18]>C(O)C>[CH3:1][N:2]([CH2:6][CH2:7][S:8][CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18])[C:3]([NH2:5])=[S:4]
Reactant: Cc1[nH]cnc1CCl
Reactant: CN(CCS)C(N)=S
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCN(C)C(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
N-Methyl-N1 -(2-mercaptoethyl)thiourea (3.85 g) in dry ethanol (10 ml) was added to a solution of sodium (1.18 g) in dry ethanol (50 ml) and the mixture was stirred at room temperature for 1 hour. 4-Chloromethyl-5-methylimidazole hydrochloride (4.29 g) was added portionwise over one hour to this stirred mixture at room temperature. The mixture was stirred at room temperature for a further hour and heated under reflux for 1/2 hour, cooled and filtered. The filtrate was evaporated to an oily solid which was recrystallised from water to give N-methyl-N1 -[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (3.2 g) m.p. 149°-151° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.N#N.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([CH3:33])[C:27]([CH3:34])=[N:26]2.C([O-])(O)=O.[Na+]>ClCCl>[CH3:33][C:28]1[C:27]([CH3:34])=[N:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([NH:22][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:24]=2)[N:29]=1
Reactant: Cc1nc2ccc(N)cc2nc1C
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)c(C)nc3c2)cc1
Yield: 89.9 %

Procedure:
To a solution of 0.4n-propylbenzenesulphonyl chloride (106 mg, 0.485 mmol) in dichloromethane (3 mL) was added pyridine (90 μL, 1.2 mmol) and the mixture was stirred under. N2 for 5 min, after which time 6-amino-2,3-dimethylquinoxaline (80 mg, 0.46 mmol) was added. The resulting mixture was stirred for 6 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (147 mg, 90%), single spot at Rf 0.69 (ethyl acetate). mp 198.4-198.8° C., HPLC purity 99+% (tR 2.39 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.86 (1H, d, J=8.9 Hz), 7.72 (2H, d, Jz;8.4 Hz), 7.56 (1H, d, J=2.5 Hz), 7.48 (1H, dd, J9.2, 2.5 Hz), 7.20 (2H, d, J=7.9 Hz), 6.82 (1H, s, N—H, 2.67 (6H, s), 2.56 (2H, t, J=7.5 Hz), 1.57 (2H, sextet, J=7.4 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 354.31 (M−). FAB-MS (MH+, C19H21N3O2S): calcd 356.1432, found 356.1433.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (1 g) in dichloromethane (16 mL) were added triethylamine (0.29 mL) and methanesulfonyl chloride (0.15 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (1.12 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (2 mL) and ethanol (2 mL). To the solution were added 2-amino-2-methyl-1-propanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.16 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.13 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:18]=[CH2:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2c1CN(Cc1ccccc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1CN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
A solution of 2-benzyl-4-bromoisoindoline (16.7 g, 58.0 mmol) and tributyl(vinyl)tin (20.3 mL, 69.6 mmol) in toluene (400 mL) was degassed by bubbling nitrogen gas through the solution for 0.25 h. Tetrakis(triphenylphosphine)palladium (0) (1.30 g, 1.16 mmol) was added and the resulting solution heated in a 100° C. oil bath under nitrogen for 24 h. The contents of the reaction flask were cooled, evaporated and subjected to flash column chromatography eluting with hexane/ethyl acetate 95/5 to give after evaporation the title compound as a pale oil that turned pink on standing. LRMS (ESI) m/z 236 [(M+H)+; calcd for C17H18N: 236].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Cl:1]
Reactant: OCCCc1ccc(C(F)(F)F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCCBr)c(Cl)c1
Reaction time: 16 h
Yield: 89 %

Procedure:
Compound 71-2 (2.48 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.00 g) and N-bromosuccinimide (2.03 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 16 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.79 g) as a colorless oil.