Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=O)[N:10]([CH3:18])[N:9]=2)=[C:4]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:26][CH2:25]3)[C:3]=12.[CH3:43][N:44]([CH3:49])[CH2:45][CH2:46][CH2:47][NH2:48]>CN(C=O)C>[CH3:43][N:44]([CH3:49])[CH2:45][CH2:46][CH2:47][NH:48][C:13]([C:11]1[N:10]([CH3:18])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[C:3]3[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]4[CH2:29][CH2:28][N:27]([C:30]5[N:34]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:33]=[N:32][N:31]=5)[CH2:26][CH2:25]4)=[CH:20][NH:19][C:4]=23)[CH:12]=1)=[O:15]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Temperature: 50 °C

Procedure:
To a sealable flask containing ethyl 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.058 g, 0.10 mmol) was added N1,N1-dimethylpropane-1,3-diamine (0.7 mL). The mixture was sealed and heated to 50° C. for 20.5 h. The mixture was cooled to rt, and was diluted with DMF and was passed through a plug of celite to remove any solids. The DMF solution was purified by prep HPLC to give N-(3-(dimethylamino)propyl)-3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide.TFA. (0.020 g) as an off-white solid. LCMS: m/e 629.5 (M+H)+, ret time 1.93 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 8.75 (s, 1H) 8.61 (s, 1H) 7.97-8.11 (m, 5H) 7.79 (s, 1H) 4.69 (s, 3H) 4.21-4.25 (m, 2H) 4.01-4.04 (m, 2H) 3.91 (t, J=6.26 Hz, 2H) 3.76-3.82 (m, J=3.66 Hz, 2H) 3.65-3.75 (m, 10H) 2.45-2.52 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[Li]CCCC.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1c[nH]c2ncccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
3 g (0.015 mol) of 2 in 20 mL of anhydrous THF was cooled to −78° C. and n-BuLi 2.5 M in hexanes (6.7 mL, 0.167 mol) was added dropwise. After 15 minutes of stirring, tosyl chloride in 5 mL of THF was added dropwise. The cooling bath was removed and the reaction mixture stirred at rt for 1 h. Extracted with ether and the organic phase washed with brine, dried with magnesium sulfate and concentrated in vacuo to give a white solid that was passed through a pad of silica (70% EtOAc; 30% Hexanes) to give 4.65 g (84%) of 3. 1H NMR CDCl3 8.4 (s, 1H), 8.1 (d, 2H), 7.8 (s, 2H), 7.2 (m, 3H), 2.3 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(N1CC[O:41][CH2:40][CH2:39]1)C.C(Cl)(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:40](=[O:41])[CH3:39])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Reactant: CCN1CCOCC1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 100.5 %

Procedure:
A mixture of 11.2 g (21.7 mmol) (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester and 50 mL dichloromethane and cooled to 0° C. in an ice/water bath. 3.2 mL (25 mmol) N-ethylmorpholine was added, followed by dropwise addition of 1.71 mL (24 mmol) acetyl chloride. After 10 min reaction time, TLC analysis showed complete reaction. The mixture was transferred to a separatory funnel and washed with 50 mL water, 50 mL brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 12 g (21.8 mmol, 100%) of (S)-3-(4-acetylamino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as a brown oil. MS (APCI) m/z 549.1 (M−1), 459.1 (M-CH2Ph).
Reaction SMILES: [Br:1]Br.[O:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[N:12]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[O:3][C:4]([N:12]3[CH:18]4[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[N:5][C:6]2=[N:7][CH:8]=1
Reactant: BrBr
Reactant: c1cnc2nc(N3CCN4CCC3CC4)oc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1

Procedure:
Bromine (0.12 mL, 2.29 mmol) was added to a solution of 4-oxazolo[4,5-b]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane (560 mg, 2.29 mmol, prepared in Example 27) and sodium acetate (2.26 g, 27.5 mmol) in water (12 mL) and acetic acid (12 mL). The resulting mixture was heated to reflux for 2 h. The mixture was cooled and extracted with ethyl acetate (3×). The combined organic layers were washed with water (2×) and brine (1×) and dried over sodium sulfate, filtered and concentrated. The crude residue was purified by chromatography (Biotage, 25M) using a gradient elution from 4% MeOH/CDCl3 containing 0.1% NH4OH to 8% MeOH/CDCl3 containing 0.1% NH4OH giving 578 mg (78%) of the title compound as an oil: 1H NMR CDCl3, 400 MHz) δ 8.23 (d, 1H, J=1.7 Hz), 7.50 (d, 1H, J=1.7 Hz), 4.51 (br s, 1H), 3.92 (br s, 2H), 3.16-3.04 (m, 4H), 3.02-2.94 (m, 2H), 2.17-2.01 (m, 2H), 1.83-1.74 (m, 2); MS (Cl) m/z 325.0/323.0 (M+1).
Reaction SMILES: Cl[CH:2]=[C:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[Na].C[O-].[Na+].N1C=CN=C1>C(#N)C.CO>[N:18]1([CH:2]=[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)C(=O)C(=Cn1ccnc1)Oc1ccc(F)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
256.7 g (1 mol) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one in 150 ml of acetonitrile were added dropwise to a suspension of 90 g (1 mol) of sodium imidazole, prepared from sodium methylate and imidazole in methanol, in 2,500 ml of acetonitrile, while stirring. Thereafter, the reaction mixture was heated to the boiling point for 6 hours. It was allowed to cool to room temperature and was concentrated by distilling off the solvent in vacuo. The residue was taken up in 1,000 ml of ethyl acetate, the mixture was washed three times with 200 ml of water each time and the organic phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 272.4 g (94.5% of theory) of crude 1-(imidazol-1-yl)-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one were obtained as a brown oil, which was purified in the customary manner, via the nitrate, and then had a refractive index of nD20 =1.5590. ##STR52##
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:16][C@H:17]([C:32]([O:34][CH3:35])=[O:33])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([C@@H:17]([C:32]([O:34][CH3:35])=[O:33])[O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:15][CH2:14]3)[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=1
Reactant: COC(=O)[C@@H](O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 70; 735 mg, 1.27 mmol) was dissolved in ethyl acetate (10 ml) with glacial acetic acid (0.5 ml) and 10% palladium hydroxide (40 mg) added. The mixture was hydrogenated on a Parr™ at 40 psi overnight. The mixture was filtered through Celite™, then concentrated in vacuo and the residue basified with saturated sodium hydrogen carbonate solution. The solution was then extracted with ethyl acetate (×3) and the extracts dried (MgSO4) and concentrated in vacuo. The obtained oil was purified by flash column chromatography [10% methanol in dichloromethane) to give the title compound as a yellow oil. (5:1 desired:undesired). (323 mg, 52%).
Reaction SMILES: [Mg].Br[C:3]1([CH3:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]1([CH2:9][C:11]2[CH2:19][C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC1(Br)CCCCC1
Reactant: BrC1=Cc2ccccc2C1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: C1=C(CC2CCCCC2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of freshly ground magnesium turnings (0.40 g, 16 mmol) in 100 mL of ether was added about 20 percent of a 100 ml ether solution containing 2.5 g (14 mmol) of bromo-methyl-cyclohexane. The reaction was heated to reflux and the remaining bromo-methyl-cyclohexane solution added over one hour. After 1 hour, an additional 150 mg of freshly ground Mg was added and after 5 hours, the mixture was cooled to room temperature. The Grignard solution was added over one hour to a mixture of 2.45 g (13 mmol) of 2-bromo-indene, 100 mg of NiCl2(dppp) (0.15 mmol) and 100 mL of ether. The system was gently heated to reflux overnight and then cooled and quenched by adding 150 mL of 1.0 M aqueous hydrochloric acid. The product was isolated and purified (hexanes/silica) as for 2-benzyl-indene.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:14])/[CH:8]=[CH:9]/[C:10]([CH3:13])([CH3:12])[CH3:11])[O:5][C:4](=[O:15])[C@@H:3]1[O:16][CH3:17].[NH2:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[NH:21][C:20]1=[O:36].C(C(CCCC)C([O-])=O)C.[Na+].C(Cl)Cl>C1COCC1>[O:36]=[C:20]1[CH:19]([NH:18][C:4](=[O:15])[C@H:3]([O:16][CH3:17])[C@H:2]([OH:1])[C@@H:6]([OH:5])[C@H:7]([OH:14])/[CH:8]=[CH:9]/[C:10]([CH3:13])([CH3:12])[CH3:11])[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[NH:21]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C(C)(C)C)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Temperature: 60 °C
Yield: 125.8 %

Procedure:
235 mg of 2 (818 μmol), 400 mg of 14 (1.59 mmol), 340 mg of sodium 2-ethylhexanoate (2.04 mmol) in 3.5 mL of THF are successively introduced into a 30 mL round-bottomed flask, with stirring and under an argon atmosphere. The mixture is heated at 60° C. for 5 h and the stirring is maintained at RT for 24 h. 15 mL of CH2Cl2 are added to the reaction medium. The mixture is washed with twice 10 mL of HCl (1N) and then 10 mL of a saturated aqueous NaCl solution. The organic phase is dried over anhydrous magnesium sulphate, filtered and then evaporated to dryness. 510 mg of crude product are obtained, which product is chromatographed on a silica cartridge (30 g, eluent CH2Cl2/MeOH 97/3). 73 mg of expected product Ex6 are recovered.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]([C:54]([F:57])([F:56])[F:55])=[N:41]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:44]4[N:40]([CH3:39])[N:41]=[C:42]([C:54]([F:57])([F:56])[F:55])[CH:43]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cn1nc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(C(F)(F)F)nn3C)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 45 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (58 mg, 0.21 mmol), sodium carbonate (22 mg, 0.21 mmols), and bis(triphenylphosphine)palladium(II) dichloride (6 mg, 0.01 mmol) in 1,2-dimethoxyethane (2.0 ml) and water (0.50 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane diethyl ether) to give 38 mg (45% yield, 66% purity) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)O)ccc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)NS(=O)(=O)c4ccccc4)ccc32)c1

Procedure:
The carboxylic acid (Example 28 ) (0.25 g) was stirred at room temperature in dichloromethane (3 ml) with benzene sulphonamide (0.10 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g) and 4-dimethylaminopyridine (0.02 g) for 144 hours. The reaction mixture was diluted with chloroform and washed with 0.5N hydrochloric acid, then water. The organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by preparative reverse-phase HPLC (1 inch LP1-ODS column), eluting with 75:25:0.1 methanol:water:acetic acid, gave N-{1-[3-(isobutoxycarbonylamino)benzyl]indol-5-ylcarbonyl}benzene sulphonamide.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].BrCC1C=CC=C(C#N)C=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2([C:27]3=[CH:28][C:29]4[O:33][CH2:32][O:31][C:30]=4[CH:34]=[C:26]3[O:25][CH2:24]2)[C:16]1=[O:35]>>[O:35]=[C:16]1[C:17]2([C:27]3=[CH:28][C:29]4[O:33][CH2:32][O:31][C:30]=4[CH:34]=[C:26]3[O:25][CH2:24]2)[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]1[CH2:2][C:3]#[N:4]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: N#CCCl
Agent: N#Cc1cccc(CBr)c1
Product: N#CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 7 and making non-critical variations using chloroacetonitrile to replace α-bromo-m-tolunitrile, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile was obtained (61%) as a colorless solid: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, 2H), 4.73 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.8, 155.8, 148.9, 142.2, 141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9, 93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].CC1(C)O[C:11](=[O:13])[CH:10]=[C:9]([CH3:14])[O:8]1>C1(C)C(C)=CC=CC=1.C(OCCCC)(=O)C.C1(=O)C=CC(=O)C=C1>[C:11]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:13])[CH2:10][C:9]([CH3:14])=[O:8]
Reactant: C=CC(N)=O
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: O=C1C=CC(=O)C=C1
Solvent: CCCCOC(C)=O
Solvent: Cc1ccccc1C
Product: C=CC(=O)NC(=O)CC(C)=O
Temperature: 80 °C
Yield: 63.2 %

Procedure:
A solution of acrylamide (21.3 g, 0.3 mol), butylated hydroxytoluene (BHT, 0.66 g, 1%) and benzoquinone (BQ, 0.22 g, 0.7%) in a mixture of 75 mL of xylene and 150 mL of n-butyl acetate was heated to about 80° C. When the reaction mixture reached 80° C., 42.6 g (0.3 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one was added as a small stream over a period of about 10 minutes; the reaction mixture was then heated rapidly up to about 120° C., and maintained at that temperature for about 10 minutes. Once heating of the reaction mixture was complete, the reaction mixture was allowed to cool and 29.4 g (63% yield; mp 128° to 130° C.) of N-acetoacetyl acrylamide was collected as a white precipitate and air dryed.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[O:9])=[C:6]([CH3:17])[CH:5]=1.ClN1C(=O)CCC1=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:35]([C:37]([F:40])([F:39])[F:38])=[CH2:36])[CH:30]=[C:31]([Cl:34])[C:32]=1[Cl:33].C(=O)([O-])O.[K+]>COCCOC.O>[CH3:17][C:6]1[CH:5]=[C:4]([C:3]2[CH2:36][C:35]([C:29]3[CH:30]=[C:31]([Cl:34])[C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=3)([C:37]([F:40])([F:39])[F:38])[O:1][N:2]=2)[CH:16]=[CH:15][C:7]=1[C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[O:9]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)NC(=O)c1ccc(C=NO)cc1C
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 23.7 %

Procedure:
In a solution of 45 mg of methyl N-[4-hydroxyiminomethyl-2-methylbenzoyl]carbamate in 10 mL of 1,2-dimethoxyethane, 40 mg of N-chlorosuccinimide was added, and stirred at 60° C. for 45 minutes. Then, the reaction mixture was left and cooled to room temperature, and then 68 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 40 mg of potassium hydrogen carbonate and 5 drops of water were added, and continued to stir at room temperature further for 15 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (15 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:2 to 1:1) to obtain 23 mg of the aimed product as colorless resinous substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:7][C:8]1[N:9]=[C:10]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1nccs1
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cccc(Nc2nccs2)n1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 1.37 g (9.26 mmol) of 2-aminothiazole, 0.74 g (7.39 mmol) of 2,6-dichloropyridine, 387 mg (0.621 mmol) of (S)-(−)-2,2′-(bisdiphenylphosphino)-1,1′-binaphthyl, 322 mg (0.311 mmol) of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 2.77 g (8.50 mmol) of cesium carbonate and 10 m1 of toluene was heated under reflux for 1 hour and 30 minutes, cooled to room temperature and diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography to give 990 mg (4.68 mmol) of the title compound as a white solid.
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].FC1C=C(F)C=C(F)C=1CBr.[CH3:18][O:19][C:20]1[C:25](C)=[CH:24][C:23]([N:27]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:30]3[CH:44]=[CH:45][CH:46]=[CH:47][C:29]=3[S:28]2(=[O:49])=[O:48])=[CH:22][C:21]=1C>CN(C=O)C>[CH3:1][O:2][C:21]1[CH:22]=[C:23]([N:27]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[C:36]([F:43])=[CH:37][C:38]([F:42])=[CH:39][C:40]=3[F:41])[C:30]3[CH:44]=[CH:45][CH:46]=[CH:47][C:29]=3[S:28]2(=[O:48])=[O:49])[CH:24]=[CH:25][C:20]=1[O:19][CH3:18]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Reactant: O=C([O-])[O-]
Agent: Fc1cc(F)c(CBr)c(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (29 mg, 0.06 mmol) was prepared from (IntA1) (84 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and 2,4,6-trifluorobenzyl bromide (68 uL, 0.30 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH3:17])=[C:11]([N+:18]([O-])=O)[CH:10]=1)=[O:7])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][CH2+:40]1SC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][C:40]1=[N:18][C:11]1[CH:10]=[C:9]([NH:8][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:7])[CH:14]=[CH:13][C:12]=1[NH:15][CH2:16][CH3:17])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)COC(C)=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.73 (1H, br s), 7.44-7.51 (3H, m), 7.23-7.34 (5H, m), 7.16 (1H, t), 7.08 (1H, dd), 7.00 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.67 (2H, s), 3.74 (3H, s), 2.98 (2H, q), 2.20 (3H, s), 1.00 (3H, t); MS(ESI): 588 (MH+).