Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Clc1cccc(CCCCc2ccccc2OCc2ccccc2)c1
Yield: 86.4 %

Procedure:
3.50 g of this 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butadiene were dissolved in 125 ml of a 4:1 by volume mixture of tetrahydrofuran and ethanol. The resulting solution was stirred for 4 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 100 mg of 5% w/w palladium-on-charcoal, whilst ice-cooling. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.06 g (yield 86%) of 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butane as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15].[CH2:16]([N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH2:17][C:18]#[CH:19]>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[I:15][C:10]1[CH:11]=[CH:12][C:13]([C:19]#[C:18][CH2:17][CH2:16][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[CH:14][CH:9]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: Ic1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution containing triethylamine (250 mL), copper (I) iodide (1.72 g, 9.09 mmol) and diiodobenzene (56) (20.00 g, 60.60 mmol) dissolved in anhydrous tetrahydrofuran (250 mL) was stirred at room temperature. The reaction flask was evacuated and then purged with nitrogen three times. The solution was treated with bis(triphenylphosphine) palladium(II) dichloride (4.20 g, 6.06 mmol) and continued to stir at room temperature for 30 min. A solution containing triethylamine (250 mL) and 2-but-3-ynylisoindole-1,3-dione (12.06 g, 60.06 mmol) dissolved in anhydrous tetrahydrofuran (250 mL) was added dropwise through an addition funnel over 12 hours. The reaction was allowed to stir at room temperature for 48 h. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 57 (12.5 g, 51%) as a brown solid: 1H NMR (500 MHz, CD2Cl2) δ 7.85 (dd, 2H), 7.74 (dd, 2H), 7.60 (d, 2H), 7.04 (d, 2H), 3.92 (t, 2H), 2.79 (t, 2H); m/z (ESI) 402 [C18H12INO2+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH3:21][NH:22][CH2:23][CH:24]1[CH:28]([CH3:29])[CH2:27][NH:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:26]2[CH2:27][CH:28]([CH3:29])[CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: CNCC1CNCC1C
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-methylaminomethyl-4-methylpyrrolidine (0.32 g) and DBU (0.25 g) was refluxed for an hour and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.31 g) as pale yellow powder, mp 253°-255° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH:16]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1.C([O:22][C:23](=O)[C:24]([F:27])([F:26])[F:25])C.C(N(CC)CC)C>CO>[N+:17]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:16][C:7]=1[O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:23](=[O:22])[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:14]1)([O-:19])=[O:18]
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1)C(F)(F)F
Reaction time: 8 h

Procedure:
A reaction mixture of 0.071 g trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexylamine hydrochlorid, 0.05 g ethyltrifluoroacetate and 0.075 g triethylamine in 2 ml methanol was stirred overnight. The mixture was concentrated and partitioned between 5 ml EtOAc and 5 ml water. The organic phase was washed with water, HCl solution (2M) and water. The organic phase was dried and the solvent evaporated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[N:19][NH:20][C:21]([NH2:23])=[S:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=NNC(N)=S)c1ccccc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
2-(tert-Butoxycarbonylamino)acetophenone (3.00 g) was dissolved in methanol (21.0 mL). To the solution was added an aqueous solution (water: 9.0 mL) of thiosemicarbazide hydrochloride (3.11 g, 24.4 mmol) at room temperature. After the mixture was stirred at the same temperature for 30 minutes, water (12.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes and then at 0° C. for 1 hour. The deposited solid was collected by filtration and washed with cooled 50% aqueous methanol (20 mL). The resulting solid was dried at 40° C. under reduced pressure to give seed crystals of 2-(tert-butoxycarbonylamino)acetophenone thiosemicarbazone (3.56 g, yield: 95.1%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)[CH3:2].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:37]([NH:36][C:30]2[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=2[F:28])=[O:38])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Solvent: ClCCl
Product: CCCCCCCN(CCOc1ccc(CC(OCC)C(=O)OCC)cc1)C(=O)Nc1ccc(F)cc1F
Reaction time: 16 h

Procedure:
A solution of the compound obtained in Step e (30.9 mg) in methylene chloride (2 ml) was added with 2,4-difluorophenyl isocyanate (14 μl, Aldrich) and stirred for 16 hours. The reaction mixture was concentrated, and the resulting residue was applied on a silica gel column and eluted with hexane/ethyl acetate (4:1) to obtain the title compound (41.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(C)(=O)=O)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of N-(3,5-dichlorobenzyl)-5-fluoro-2-(methylsulfonyl)benzenamine (2.1 mmol), t-butyl piperazine-1-carboxylate (2.2 mmol), N,N-diisopropylethylamine (4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (23%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1 H), 7.67 (d, 1 H), 7.31 (s, 1 H), 7.21 (s, 2 H), 6.13 (dd, 1 H), 5.70 (d, 1 H), 4.42 (d, 2H), 3.54 (m, 4 H), 3.38 (m, 4 H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 514.47; Observed: 515.6 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].C([N:36](CC)CC)C.N#CBr>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]#[N:36])[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1
Reactant: CCN(CC)CC
Agent: N#CBr
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C#N)CC3)cn2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.1 %

Procedure:
To a stirred solution of tert-butyl 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)-piperidine-1-carboxylate (0.3 g, 0.63 mmol) in dichloromethane (5 mL) trifluoroacetic acid (2.0 mL) was added at 0° C. and stirred at room temperature for 2-3 h. The solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane (5 mL), triethylamine (0.193 g, 1.91 mmol) and the cyanogen bromide (0.101 g, 0.95 mmol) were added at 0° C. and stirred at room temperature for 2-3 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to give 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidine-1-carbonitrile (0.160 g, 63%); MS: 397 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(CCl)cc1
Product: CCOP(=O)(Cc1ccc(OC)cc1)OCC

Procedure:
4-methoxybenzylchloride and triethyl phosphite were reacted for 5 hrs at 150° C. Then the excessive triethylphosphite and a by product ethyl chloride were removed by reduced-pressure distillation to prepare diethyl 4-methoxybenzylphosphonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=O)cc2)CC1

Procedure:
To N-t-butyloxycarbonylpiperidin-4-ylmethanol (7.87 g, 36.5 mmol), p-hydroxybenzaldehyde (4.46 g, 36.5 mmol) and PPh3 (9.59 g, 36.5 mmol) in THF (100 mL) at -20° C. was added DEAD (5.75 mL, 36.5 mmol) in THF (50 mL) according to Example 1, Part B, affording 8.14 g (70%); mp: 115.6°-116.8° C.; 1H NMR (300 MHz, CDCl3) δ 9.86 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.15 (bd, J=13.2 Hz 2H), 3.87 (d, J=6.6 Hz, 2H), 2.74 (dt, J=12.4, 1.8 Hz, 2H), 1.97 (m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.27 (dq, J=12.1, 4.0 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)(=[O:8])=[O:7]>C(O)C.CC(O)=O.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([S:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Yield: 99.7 %

Procedure:
A solution of 3 (0.8 g) in ethanol (10 mL) was subjected to catalytic hydrogenation (10% Pd/C, Degussa, 0.8 g, 3 drops of AcOH, 1 atm.) overnight. To work up, the solids were filtered the filtrate was dried under vacuum to afford 4 as a solid (0.71 g) which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1.O>CN(C=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=C1CCC(=O)N1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
To a solution of 102 (200 mg, 0.481 mmol, scheme 26) in DMF (5 mL) was added Cs2CO3 (313 mg, 0.962 mmol) and succinimide (95 mg, 0.962 mmol) and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 138 (100 mg, 43% yield) that was triturated with Et2O and used with no additional purification. MS (m/z)=479.50 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH:25]([OH:38])[CH:26]([NH:29][C:30](=[O:37])[CH:31]([NH2:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH3:28].C(N(C(C)C)CC)(C)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:1]([O:3][C:4](=[O:14])[N:5]=[C:6]([NH:36][C@H:31]([C:30](=[O:37])[NH:29][C@H:26]([C:25]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)=[O:38])[CH2:27][CH3:28])[CH2:32][CH:33]([CH3:34])[CH3:35])[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCC(NC(=O)C(N)CC(C)C)C(O)c1nc2ccccc2o1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N=C(N[C@@H](CC(C)C)C(=O)N[C@@H](CC)C(=O)c1nc2ccccc2o1)N1CCOCC1
Temperature: 25 °C

Procedure:
(Morpholine-4-carbothioyl)carbamic acid ethyl ester (55 mg, 0.25 mmol), 2-amino-4-methylpentanoic acid [1-(benzoxazol-2-ylhydroxymethyl)propyl]amide hydrochloride (90 mg, 0.25 mmol), and diisopropylethylamine (0.13 mL, 0.76 mmol) were dissolved in dichloromethane (5 mL). 2-Chloro-1-methylpyridinium iodide (84 mg, 0.33 mmol) was added and the reaction mixture was stirred at ambient temperature over night. After dilution with ethyl acetate (100 mL), the solution was washed with sat. aq. NaHCO3, and brine, dried with MgSO4 and evaporated under vacuum. The residue was dissolved in dichloromethane (10 mL) and Dess-Martin periodinane (400 mg) was added. The reaction mixture was stirred at ambient temperature for 1 h. After dilution with ethyl acetate (100 mL), the solution was washed with a 0.26 M solution of Na2S2O3 in sat. aqu. NaHCO3, then with sat. aq. NaHCO3, and brine, dried with MgSO4 and evaporated under vacuum. After purification by flash chromatography on silica gel, the title compound was obtained as yellowish glass (10 mg, 0.020 mmol). MS: (M+H)+ 502.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][N:8]=1>CN(C=O)C>[Br:3][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: Cc1cnc(Br)c([N+](=O)[O-])c1
Temperature: 5 °C
Yield: 85.8 %

Procedure:
POBr3 (222.8 g, 0.78 mol) was added in portions to 2-hydroxy-5-methyl-3-nitropyridine (100 g, 0.65 mol) in DMF (500 mL) with stirring at 0-10° C. then the reaction mixture was stirred at 80° C. under nitrogen for 12 h. Reaction mixture was cooled and poured into crushed ice (1 Kg), obtained solid was filtered, washed thoroughly with ice-cold water (2×500 mL), dried in a desiccator under high vacuum for one day to obtain 2-bromo-5-methyl-3-nitropyridine as yellow solid (121 g) in 86% yield. (M+H) Expected: 217. found 216.9.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.C([Mg]Cl)(C)C.CO[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:3]=[N:4]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (Stage 106.1.3, 8.50 g, 26.4 mmol) in THF at 0° C. under argon was added dropwise iPrMgCl 2 M in THF (26.4 ml, 52.8 mmol). The RM was stirred at 0° C. for 1 h. Then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Aldrich, Buchs, Switzerland, 6.25 g, 52.8 mmol) was added at 0° C. and the solution was stirred again and allowed to warm to rt for 1 h. After that, the RM was quenched with saturated aqueous NH4Cl (140 ml) and extracted with EtOAc (3×). The combined organic layers were washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (hexane/EtOAc 5% to 45%). The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil. (HPLC: tR 3.23 min (Method A); M+H=323 MS-ES)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:22]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH2:23][CH2:24][C:25](OC1C=CC=CC=1)=[O:26].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(Cc2c[nH]c3ccccc23)c1
Reactant: O=C(CCC(=O)Oc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCC(=O)n1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.1 %

Procedure:
A solution of 3-(3-nitrobenzyl)indole (280 mg) in N,N-dimethylforma/nide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 66.6 mg) in N,N-dimethylformamide (10 ml) at 0° C. The mixture was stirred at 25° C. for 40 minutes, and a solution of benZyl phenyl succinate (316 mg) in N,N-dimethylformamide was added at -40° C. After stirred at -40° C. for 20 minutes, the reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over, magnesium sulfate. After evaporation of the solvent, the crude crystals were washed with hot isopropyl ether to give benzyl 4-[3-(3-nitrobenzyl)indol-l-yl]-4-oxobutyrate (364 mg).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][NH:10][C:9](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.S(Cl)([Cl:21])=O>ClC1C=CC=CC=1>[Cl:21][C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[S:11][N:10]=1
Reactant: O=c1[nH]sc2c([N+](=O)[O-])cccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cccc2c(Cl)nsc12
Reaction time: 1 h
Yield: 86 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 98.1 g (0.5 mol) of 7-nitro-1,2-benzisothiazol-3-one, 146.2 g (2 mol) of N,N-dimethylformamide and 500.0 g of chlorobenzene. While stirring, 119.0 g (1.0 mol) of thionyl chloride was added dropwise thereto at 80° to 90° C. over 1 hour, and the mixture was reacted at the same temperature for 3 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was recrystallized from toluene to give 91.2 g (0.43 mol) of 3-chloro-7-nitro-1,2-benzisothiazole. The yield based on 7-nitro-1,2-benzisothiazol-3-one was 85%.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li]CCCC.[CH3:21][CH:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:23]([OH:31])([CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1)[CH:22]([CH3:21])[CH3:32])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)CCc1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)C(O)(CCc1ccsc1)CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in General Method 9 using t-butyl acetate (42.6 mmol), diisopropyl amine (42.6 mmol), nBuLi (42.6 mmol), 4-methyl-1-thiophen-3-yl-pentan-3-one (Example C-5; 21.3 mmol), and THF (100 mL). The title compound was purified by flash chromatography over silica gel eluting with hexane:EtOAc 97:3. 1NMR (CDCl3): δ0.95 (dd, 6 H), 1.47 (s, 9 H), 1.7-2.0 (m, 3 H), 2.36-2.54 (AB q, 2 H), 2.6-2.8 (m, 2 H), 6.93-6.95 (m, 2 H), 7.23-7.25 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH2:27])=[O:26])=[C:20]([F:28])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[CH:29][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[O:26])=[C:20]([F:28])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: NC(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)NC(=O)c1c(F)cccc1F
Temperature: 20 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
2,6-Difluorobenzoyl isocyanate (1.8 g) was added to a solution of N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)-2-fluorophenyl)urea (3.2 g) in dry toluene (50 ml), and the resulting solution was stirred at ambient temperature (20° C.) for 48 hours. The product was then filtered from the reaction mixture, washed with a small amount of 1:2 v/v diethyl ether/light petroleum ether, and dried to yield N-(((((4-(2-chloro-4-(trifluoromethyl)phenoxy)-2-fluorophenyl)-amino)carbonyl)amino)carbonyl)-2,6-difluorobenzamide as a colourless crystalline solid (4.3 g, 90%), mp 190-192° C.