Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1)[CH2:5][CH3:6].C(N(CCN[C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=2)[N:36]=1)=[O:34])CCOC1C(F)=NC=CC=1)C>>[Br:16][C:12]1[N:11]=[C:10]([NH:9][CH2:8][CH2:7][N:4]([CH2:3][CH2:2][NH:1][C:33]([C:35]2[CH:44]=[N:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=3)[N:36]=2)=[O:34])[CH2:5][CH3:6])[CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CCN)CCNc1cccc(Br)n1
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCNc1cccc(Br)n1
Yield: 70 %

Procedure:
This compound was prepared, starting from compound 62 (120 mg, 0.42 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 7 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 63 (166 mg, 0.33 mmol) as a yellow solid. Yield 70%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.34; mp 49-51° C.; IR (KBr) ν 1160, 1594, 1671, 2750-3000, 3200-3400 cm−1: 1H NMR (400 MHz, CDCl3) δ 1.04 (t, 3H, J=7.1 Hz), 2.64 (q, 2H, J=7.1 Hz), 2.74 (m, 4H), 3.27 (q, 2H, J=5.3 Hz), 3.57 (q, 2H, J=5.8 Hz), 5.32 (m, 1H), 6.16 (d, 1H, J=8.1 Hz), 6.56 (d, 1H, J=7.4 Hz), 7.05 (t, 1H, J=7.8 Hz), 7.81 (d, 1H, J=8.8 Hz), 8.05 (dd, 1H, J=1.9, 8.8 Hz), 8.25 (m, 1H), 8.55 (d, 1H, J=1.9 Hz), 9.58 (s, 1H); ESI-MS m/z 568.9 [M+H]+.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]([O:16][C:17]([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])=[O:18])[CH3:15]>C(O)C>[CH2:1]([N:7]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:25]([OH:26])=[C:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])[C:20]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CCCCCCNc1ccccc1
Solvent: CCO
Product: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21

Procedure:
In a round-bottomed flask equipped with a condenser, N-hexylaniline (355 mg, 2 mmol) is added to a solution of methanetricarboxylic acid triethyl ester (1.35 ml, 6.4 mmol). The resulting reaction mixture is placed in a CEM Discovery microwave oven and irradiated in the open round-bottomed flask, and then the ethanol formed is distilled off (the parameters are the following: power=250 W, temperature=225° C., execution time=5 min, hold time=15 min).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Nc2nc(C(Cl)(Cl)Cl)ns2)cc1

Procedure:
A solution of 11.0 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 8.0 g (0.05 mole) 4-toluoyl chloride in 250 ml toluene was heated at reflux for 20 hours. Unreacted amino compound was removed by cooling the reaction mixture and filtering the precipitate. Concentration of the filtrate in vacuo gave the crude product, which was purified by recrystallization from cyclohexane. Yield was 9.1 g (27%); m.p. 127° C.
Reaction SMILES: [C:1]([C:9]1[N:10]([CH2:20][C:21]([OH:23])=O)[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:37][C:38]([NH2:40])=[NH:39].C(N(CC)CC)C>CN(C=O)C>[NH2:39][C:38](=[NH:37])[NH:40][C:21](=[O:23])[CH2:20][N:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=[C:9]1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: O=C(O)Cn1c(C(=O)c2ccccc2)ccc1-c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(N)NC(=O)Cn1c(C(=O)c2ccccc2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of tert-butyl(2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetate (148 mg, 0.41 mmol) in trifluoroacetic acid was stirred for 2 h at room temperature. After removal of trifluoroacetic acid, the residue was treated with CH2Cl2 (10 ml), MeOH (1 ml) and H2O (10 ml). The two layers were separated and the aqueous was extracted with CH2Cl2 (3×10 ml). The combined organic extracts were washed with H2O (10 ml), brine (10 ml), dried (Na2SO4) filtered and concentrated. The crude material was purified by chromatography (silica gel, EtOAc/hexane/HCO2H: 10/40/0.1) to afford (2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (125 mg, 100%) as an oil. To a stirred solution of (2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (260 mg, 0.85 mmol) in DMF (2.0 ml) was added 1,1′-carbonyldiimidazole (166 mg, 1.02 mmol) at room temperature. After stirring for 1 h, the reaction mixture was treated with a solution of guanidine hydrochloride (244 mg, 2.55 mmol) in DMF (2.5 ml) and triethylamine (0.54 ml, 2.55 mmol). After stirring over night, the reaction mixture was quenched with H2O (30 ml). The aqueous was extracted with Et2O (3×30 ml), EtOAc (10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/hexane/2M NH3 in MeOH: 65/35/1) to give the titled compound (169 mg, 58%) as a white solid: mp 201-203° C.; MS (−) ES, 345 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].[CH3:27][C:28]1([CH3:45])[O:32][C@H:31]([CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30][O:29]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:45])([CH3:27])[O:32]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)O1
Temperature: 25 °C
Reaction time: 28 h
Yield: 50 %

Procedure:
A solution of 6.26 g (20.00 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) in 200 ml of THF was treated at 0° C. with 2.47 g (22.00 mmol) of potassium tert-butylate and after 10 min with 5.73 (20.00 mmol) of toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester. The reaction was stirred for 14 h at RT, 28 h at reflux temperature, cooled and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/MeOH 97.5/2.5) to yield 4.27 g (50%) of the title compound as off-white powder. MS: 427.1 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22]CC)=[O:21])[C:15]2=[O:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:25]([CH3:27])[CH3:26])[C:20]([OH:22])=[O:21])[C:15]2=[O:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(C)C)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(C(=O)O)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Ethyl 2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (0.330 g; 0.80 mmol) was dissolved in methanol (MeOH; 6 ml). NaOH solution (1N; 3 ml) as added, and the mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure, and saturated NaH2PO4 solution (2 ml) was added to he residue. The solid was filtered off with suction and dried under reduced pressure at 60° C. to result in 2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (0.25 g; 0.66 mmol). MS: 383.10 (M+H); Rt: 1.57 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8](CC3C=CC=CC=3)[CH2:9][C@@H:4]2[CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O[C@@H]1C[C@H]2CNCCN2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.75 g (42.0 mmol) of (7R,8aS)-7-hydroxy-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Diafi, L. et al., J. Het. Chem., 1990, 27, 2181) and 29.4 mL of 5M ammonium formate in 140 mL of methanol was treated with an aqueous slurry of 4.9 g of 10% palladium on carbon and the mixture was stirred at ambient temperature for 18 hours. The mixture was filtered through Celite and evaporated to give (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine as a clear oil.
Reaction SMILES: [CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C@@H:54]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=1>C(Cl)Cl>[CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH:53][C@@H:54]([CH2:68][C:69]3[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=3)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=3)=[O:18])[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)c1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(C)c1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[butyl(methyl)amino]isoquinoline-7-carboxylic acid (130 mg, 0.5 mmol) and N,N-diisopropylethylamine (525 μL, 3.0 mmol)in methylene chloride (6.25 mL) was added HBTU (190 mg, 0.5 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (174 mg, 0.42 mmol) was added in one portion and the reaction mixture was stirred at room temperature 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1-5% methanol in chloroform) gave 1-[butyl(methyl)amino]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([NH:15][C@@H:16]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (128 mg, 630 μmol, Eq: 1.5), (S)-ethyl 1-((S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (140 mg, 420 μmol, Eq: 1.00) and HATU (240 mg, 630 μmol, Eq: 1.5) were combined with DMF (2 mL) to give a light yellow solution. Diisopropylethylamine (110 μL, 630 μmol, Eq: 1.5) was added and the reaction was stirred at rt over the weekend. The reaction mixture was partitioned between EtOAc and water and the separated organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (188 mg), m/z=519 (M+H).
Reaction SMILES: C(O)C.O1CCCC1.[C:9]([N:17]1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]2)[S:20][CH2:19][C@H:18]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(OCC)(=O)C.O>[C:9]([N:17]1[C:21]2([CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)[S:20][CH2:19][C@H:18]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1CCC2(CC1)SC[C@@H](C(=O)OC(C)(C)C)N2C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CSC2(CCC(C(=O)O)CC2)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
In a mixture consisting of 23 ml of ethanol and 23 ml of tetrahydrofuran was dissolved 2.30 g of ethyl (3R)-4-benzoyl-3-(tert-butoxycarbonyl)-1-thia-4-azaspiro[4.5]decane-8-carboxylate. Then, 15.9 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C. and the resulting mixture was stirred at ambient temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue thus obtained was added to a mixture of water and ethyl acetate, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Isopropyl ether was added to the residue and the deposited crystal was collected by filtration. Thus, 1.78 g of (3R)-4-benzoyl-3-(tert-butoxycarbonyl)-1-thia-4-azaspiro[4.5]decane-8-carboxylic acid was obtained as a colorless crystalline product.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:31][C:32]1[N:33]=[CH:34][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])=[CH:36][CH:37]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(Cl)nc2)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 2-chloropyridine-5-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a light brown solid (19%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15]([CH2:17]O)=[N:16][C:12]=2[CH:11]=1.C(Cl)(=O)C(Cl)=O.[I-].[Na+].[CH3:35][NH:36][CH3:37]>CN(C)C=O.C(Cl)(Cl)Cl.O1CCCC1.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15]([CH2:17][N:36]([CH3:37])[CH3:35])=[N:16][C:12]=2[CH:11]=1
Reactant: CNC
Reactant: OCc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 25 °C
Yield: 38 %

Procedure:
An eggplant flask was charged with 5-(benzothiazol-2-yl)-2-hydroxymethyl-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 8) (0.431 g, 1.179 mmol), oxalyl chloride (0.178 g, 1.40 mmol), and anhydrous dichloromethane (22 mL), and after the addition of anhydrous N,N-dimethylformamide (5 drops) at room temperature, this was refluxed for 3.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. To the yellow residue was added anhydrous tetrahydrofuran (1 mL) and anhydrous sodium iodide (0.267 g, 1.78 mmol), followed by a tetrahydrofuran solution of dimethylamine (2.0 M, 5 mL), and this was refluxed for 16 hours. After being allowed to cool to room temperature, the solvent was distilled off under reduced pressure. An adsorbed silica gel powder was prepared from the yellow residue (0.8 g) using chloroform (approx. 30 mL) and silica gel (3.2 g), and this was purified by silica gel column chromatography (silica gel: 32 g, MeOH/CHCl3=1/20) to yield the title compound (0.176 g, 38.0% yield) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.P([Cl:32])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:32])[C:2]([F:15])([F:14])[F:1])=[CH:7][CH:8]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Temperature: 82 °C
Yield: 83.6 %

Procedure:
Five grams (22.8 mmol) of 2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide, 12.26 g (45.6 mmol) of diphenyl chlorophosphate, 4.62 g (45.6 mmol) of triethylamine, and 25 ml of acetonitrile were introduced into a 100 ml flask and reacted for 22 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.53 g of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 83.6%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=1>C(#N)C1C=CC=CC=1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:20][CH:19]=1
Reactant: C#CCCCCCC
Reactant: N#Cc1ccc(F)cc1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccc(F)cc1
Reaction time: 45 h
Yield: 67 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-fluorobenzonitrile (0.242 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 45 h at 65° C. showed the presence of 1.34 mmol (67% yield) of 1-fluoro-4-(1-octynyl)benzene and no remaining 4-fluorobenzonitrile in the reaction mixture.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[Cl:31]>CN(C=O)C>[CH3:11][C:10]1([CH3:12])[O:9][B:8]([OH:13])[C:7]2[CH:14]=[CH:15][C:4]([C:3]3[CH2:25][C:24]([C:22]4[CH:21]=[C:20]([Cl:30])[C:19]([Cl:31])=[C:18]([Cl:17])[CH:23]=4)([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=3)=[CH:5][C:6]1=2
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (850 mg, 3.55 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.47 g, 5.32 mmol) in DMF (10 mL) at rt was added TEA (0.5 mL, 3.55 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired title compound 3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (510 mg; 30% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.86 (s, 2H), 7.78 (s, 2H), 7.72 (d, J=7.2 Hz, 1H), 4.46 (d, J=19.2 Hz, 1H), 4.35 (d, J=18.4 Hz, 1H), 1.49 (s,6H) ppm; HPLC purity: 95.3% at 220 nm and 96.8% at 254 nm; MS: m/z=478.4 (M+, ESI+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[OH:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][OH:17])=[CH:28][CH:27]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(OCCO)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(OCCO)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4(2-hydroxyethoxy)benzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C21 was scraped and collected. (100 mg)