Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=S)[C:12]([C:21](OCC)=[O:22])=[CH:11]2)=[CH:5][CH:4]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35].C(=O)([O-])[O-].[K+].[K+].NN.C(=O)(O)[O-].[Na+]>C(O)C>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:21](=[O:22])[C:12]2=[CH:11][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]2=[N:35]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=S
Agent: Cl
Agent: NN
Agent: O=C([O-])O
Solvent: CCO
Product: COc1ccc(Cn2cc3c(=O)n(-c4ccccc4F)nc-3c3ccccc32)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
Ethyl {[4-(methoxy)phenyl]methyl}-4-thioxo-1,4-dihydroquinoline-3-carboxylate (128 mg, 0.362 mmol), 2-fluorophenylhydrazine hydrochloride (88. mg, 0.543 mmol, 1.5 equiv) and potassium carbonate (250 mg, 1.81 mmol, 5 equiv) were combined in absolute ethanol (5 mL) and placed into an oil bath preheated at 70° C. for 14 hours. Additional hydrazine (120 mg, 1.09 mmol, 3 equiv) was added and the mixture was heated for an additional 24 hours at 70° C. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (1×75 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 9.10 (1H, s), 8.19 (1H, dd, J=8.0, 1.3 Hz), 7.81 (1H, d, J=8.7 Hz), 7.64-7.58 (2H, m), 7.53 (1H, t, J=7.6 Hz), 7.47-7.43 (1H, m), 7.40 (1H, ddd, J=10.2, 8.3, 1.3 Hz), 7.35-7.31 (1H, m), 7.30 (2H, d, J=8.6 Hz), 6.92 (2H, d, J=8.6 Hz), 5.66 (2H, s), 3.71 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 400.1461 [(M+H)+; calculated for C24H18FN3O2: 400.1456].
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17](OC(C)=O)=[O:18]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:17](=[O:18])[CH3:16])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled suspension of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (15 g) in DCM (300 mL) was added Ac2O (10.8 mL) followed by TEA (2.19 mL), and the resulting mixture was stirred at RT for 3 h. The reaction mixture was then partitioned between DCM and water, and isopropyl amine was added to facilitate the separation. The organic layer was washed with dilute aqueous NaHCO3, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated with Et2O, the solid was collected by filtration and dried under reduced pressure to afford 14.3 g of (4-acetylamino-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH:19]([CH:21]1[NH:26][CH2:25][CH2:24][NH:23][CH2:22]1)=[CH2:20]>N1C=CC=CC=1>[CH:19]([CH:21]1[NH:26][CH2:25][CH2:24][N:23]([C:10]2[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:14])[CH2:22]1)=[CH2:20]
Reactant: C=CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Temperature: 100 °C
Yield: 12.2 %

Procedure:
A mixture of 1.2 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.9 g of 3-ethenylpiperazine and 15 ml of pyridine is heated at 100° C. in a pressure bottle for 3 hours, then cooled and evaporated. The residue is purified by silica gel flash chromatography, eluting with chloroform:methanol:water:triethylamine (9:0.5:0.02:0.02), giving 200 mg of the desired product.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[I-].[C:18]([CH2:20][P+](C)(C)C)#[N:19].C(N(C(C)C)CC)(C)C.O>C(#N)CC>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][CH2:20][C:18]#[N:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: O
Product: N#CCCc1c2ccccc2cc2ccccc12
Temperature: 97 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
To a solution of anthracen-9-yl-methanol (6.58 g, 31.6 mmol) and (cyanomethyl)trimethylphosphonium iodide (19.19 g, 78.96 mmol) in propionitrile (77 mL) was added diisopropylethylamine (DIPEA, 49.4 mL, 94.74 mmol) and the mixture was stirred at 97° C. for 20 hours. Water (3.82 mL) was added, nitrogen was bubbled though the mixture, and the mixture was stirred for 20 hours. Water (480 mL) and concentrated HCl (19 mL) were added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting solid was purified by silica gel column chromatography (hexane:CHCl3=1:1) to give 3-anthracen-9-yl-propionitrile as brown crystals (6.93 g, 95% yield). 1H NMR (CDCl3) δ 8.43 (1H, s), 8.19 (2H, d), 8.05 (2H, d), 7.60 (2H, dd), 7.51 (2H, dd), 4.02 (2H, t), 2.79 (2H, t).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)([OH:22])=[O:21]>C(O)C.C1(C)C=CC=CC=1>[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:15]/[C:9]2[C:10](=[O:14])[O:11][C:12]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=3)=[CH:32][CH:33]=1)([OH:22])=[O:21]
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Reactant: Cc1cc[n+](CCCCCC(=O)O)cc1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)cc3)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-4-methyl-pyridinium bromide are converted according to the general directions above. Column chromatography: SiO2, eluent: ethanol/toluene.
Reaction SMILES: [Cs].C(C1C=C(O)C=C2C=1C(=O)NS2(=O)=O)(C)C.C(Br)C1C=CC=CC=1.[CH2:26]([N:33]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][C:39]([OH:48])=[CH:40][C:41]=2[CH:45]([CH3:47])[CH3:46])[S:34]1(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:49]([N:51]([CH2:55][CH3:56])[C:52](Cl)=[S:53])[CH3:50]>CN(C=O)C>[CH2:26]([N:33]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][C:39]([O:48][C:52](=[S:53])[N:51]([CH2:55][CH3:56])[CH2:49][CH3:50])=[CH:40][C:41]=2[CH:45]([CH3:46])[CH3:47])[S:34]1(=[O:36])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCN(CC)C(=S)Cl
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(Cc1ccccc1)S2(=O)=O
Agent: BrCc1ccccc1
Agent: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Agent: [Cs]
Solvent: CN(C)C=O
Product: CCN(CC)C(=S)Oc1cc(C(C)C)c2c(c1)S(=O)(=O)N(Cc1ccccc1)C2=O

Procedure:
Selective N-benzylation of the cesium salt of 4-isopropyl-6-hydroxysaccharin (Preparation 19) with benzyl bromide and reaction of the 2-benzyl-4-isopropyl-6-hydroxysaccharin with N,N-diethylthiocarbamyl chloride in DMF using the procedure described above in Preparation 12 affords 2-benzyl-4-isopropyl-6-(N,N-diethylthiocarbamyloxy)saccharin which, on heating, rearranges to 2-benzyl-4-isopropyl-6-(N,N-diethylcarbamyl-thio)saccharin. The latter, on hydrolysis with alkali, affords 2-benzyl-4-isopropyl-6-mercaptosaccharin which on reaction with methyl iodide, and transfer hydrogenolysis affords 4-isopropyl-6-methylthiosaccharin. Oxidation of the latter with one or two molar equivalents of 3-chloroperbenzoic acid affords 4-isopropyl-6-methyl-sulfinylsaccharin and 4-isopropyl-6-methulsulfonyl-saccharin.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:15][S:16](O)(=[O:18])=[O:17].C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 1.84 g (10.0 mmol) of 4-methyldiphenyl ether (see J. Chem Soc., Perkin Trans. 1, 1992, 407-408) with 2 mL of dichloromethane in an ice-bath was added a solution of chlorosulfonic acid (0.73 mL, 11.0 mmol) in 2 mL of dichloromethane dropwise. The resulting mixture was stirred at 0° C. to room temperature for 2 hours, and then oxalyl chloride (11.14 mL, 13.0 mmol) was added dropwise, followed by 0.15 mL of DMF. The resulting mixture was heated to 40° C. for 1 hour and then allowed to cool to room temperature over a 2 hour period. The reaction mixture was poured into ice-pH 7 phosphate buffer (50 mL), then extracted with EtOAc:Hexane (4:3) (3×150 mL). The combined organic layers were washed with brine (75 mL). The aqueous layer was extracted with EtOAc/Hexane(4:3) (150 mL). The organic layer was dried over Na2SO4, then evaporated by vacuum to give crude product as white solid. This solid was triturated with hexane and collected by filtration, then dried under high vacuum to give 1.555 g (57%) of 4-(4-methylphenoxy)benzenesulfonyl chloride as white solid: mp 295-300° C. 1H-NMR (DMSO-d6) δ 2.34 (s, 3H), 6.91-6.99 (dd, J=7.7, 8.4 Hz, 4H), 7.24-7.27 (d, J=8.4 Hz, 2H), 7.61-7.63 (d, J=8.1 Hz, 2H).
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Li+].[OH-].Cl>CO.O>[OH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
Intermediate B (5 g, 25.7 mmol) was dissolved in MeOH (50 mL) and water (10 mL). LiOH (1.85 g, 77.2 mmol) was added and the reaction stirred at RT for 18 h. The reaction mixture was acidified to pH˜3 with 1M HCl, the resulting precipitate was isolated by filtration to afford the desired product (4.57 g, quant.). 1H NMR (300 MHz, d6-DMSO) δ: 7.18 (4H, q), 4.45 (2H, d), 2.81 (2H, t), 2.62 (2H, t).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[O:10][CH2:11][C:12](=[N:14][OH:15])[NH2:13].[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33](O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN=C=NCCCN(C)C.Cl>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[O:10][CH2:11][C:12]1[N:13]=[C:33]([C@@H:29]2[CH2:30][CH2:31][CH2:32][N:28]2[C:26]([O:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:27])[O:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(OCC(N)=NO)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(OCc2noc([C@@H]3CCCN3C(=O)OC(C)(C)C)n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.6 %

Procedure:
To a CHCl3 (20 ml) solution of the compound (1.0 g) obtained in Example 12-(1) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.0 g), WSC.HCl (1.0 g) was added and the mixture was stirred at room temperature for 4 hours. Water was added, followed by extraction with CHCl3. After distilling off the solvent under reduced pressure, the residue was dissolved in toluene (20 ml), followed by refluxing for 2 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (190 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].C(N(C(C)C)C(C)C)C>CS(C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: Nc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Nc4ccccn4)n3)cc2s1
Temperature: 180 °C
Yield: 9.2 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), pyridin-2-amine (0.03 g, 0.3 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 g, 1.0 mmol) in DMSO (1 g, 13 mmol) was heated under microwave (CEM) at 180° C. and 200 W (Powermax® off). Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC to give a light yellow solid (10 mg). MS (ESI pos. ion) Found m/z: 363, (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[Li]CCCC.Cl[Si](C)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[C:8]=1[C:24]1([OH:27])[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[NH2:5]
Reactant: CN1CCC(=O)CC1
Reactant: Nc1cc(F)cc(F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2c(F)cc(N)cc2F)CC1
Temperature: -74 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (7.0 g, 54 mmol) in anhydrous THF (250 ml) under an atmosphere of nitrogen and cooled to −74° C. was added dropwise nBuLi (1.45M in hexanes, 78.6 ml, 0.114 mol) over a period of 10 minutes. The reaction was allowed to stir at −74° C. for 30 minutes. Chlorotrimethylsilane (12.4 g, 0.114 mol), in anhydrous THF (100 ml) was added dropwise over a period of 10 minutes. The solution was allowed to warm to ambient temperature and then stir for 40 minutes. The reaction was then cooled again to −74° C. and nBuLi (1.45M in hexanes, 43.0 ml, 62.4 mmol) was added dropwise over a period of 10 minutes. After stirring for a further 3.5 hours at −74° C., N-methyl-4-piperidone (7.90 g, 70.5 mmol) in anhydrous THF (50 ml) was added dropwise over a period of 10 minutes. The reaction was allowed to stir to ambient temperature over the weekend. The reaction was acidified with 10% HCl to pH<1 and extracted with diethyl ether. The aqueous phase was separated and treated with 40% NaOH to pH 12 then extracted with diethyl ether and the combined organic phases were washed with sat NaCl and then dried over MgSO4 and evaporated under reduced pressure. The resulting brown oil was triturated with cyclohexane to give the title compound as a pale yellow solid (9.30 g, 71%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCCCCCCc1ccco1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCc1ccco1

Procedure:
19 g of 8-(2-furyl)-octanoic acid were refluxed for 4 hours with 100 ml of methanol and 1.5 ml of sulphuric acid. The mixture was then evaporated to one third of its original volume. 100 g. of ice-water were then added, whereupon the mixture was extracted with ether.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:28]([CH3:29])=[CH:27][C:26]([C:30](O)=[O:31])=[N:25]1)=[O:14].[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:33]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:30]([C:26]1[CH:27]=[C:28]([CH3:29])[N:24]([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:13]([N:4]2[C@H:3]([CH2:2][OH:1])[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[N:25]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: Cc1cc(C(=O)O)nn1-c1ccc([N+](=O)[O-])cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Reactant: CCCCNCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (5)-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (14.0 g, 32.1 mmol) in DMF (150 mL) were added dibutylamine (8.6 mL, 48.2 mmol), EDC.HCl (9.2 g, 48.2 mmol), HOBT (5.63 g, 41.7 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (300 mL×2) twice. The combined organic layers were washed with water (300 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as and ‘off white’ solid 9 g (51%). Rf=0.47 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.62-8.22 (m, 2H), 8.00-7.80 (m, 1H), 7.30-6.84 (m, 4H), 6.60-6.35 (m, 1H), 5.20-3.80 (m, 3H), 3.79-2.40 (m, 9H), 2.38-2.20 (m, 3H), 1.60-0.50 (m, 14H); LC-MS: m/z 548.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][Sn:11]([N:14]=[N+:15]=[N-:16])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[N:14]([Sn:11]([CH3:13])([CH3:12])[CH3:10])[N:15]=[N:16][N:5]=1
Reactant: N#Cc1ccccc1Br
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: C[Sn](C)(C)n1nnnc1-c1ccccc1Br
Temperature: 25 °C

Procedure:
To a solution of 1.50 g of o-bromobenzonitrile in 8.0 ml of toluene is added 1.70 g of trimethyltin azide. The reaction mixture is heated to reflux for 18 hours and then allowed to cool to room temperature. The resulting white precipitate is isolated by filtration and used without purification in the next step.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C@@H:8]([C@@:10]1([CH3:31])[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH2:13][N:12]([C:24](=[O:30])[CH2:25][S:26][C:27](=[O:29])[CH3:28])[CH2:11]1)[CH3:9].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>CN(C=O)C.O>[OH:7][C@@H:8]([C@@:10]1([CH3:31])[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:35][CH:32]3[CH2:34][CH2:33]3)[CH:16]=2)[CH2:13][N:12]([C:24](=[O:30])[CH2:25][S:26][C:27](=[O:29])[CH3:28])[CH2:11]1)[CH3:9]
Reactant: BrCC1CC1
Reactant: COc1ccc([C@@H]2CN(C(=O)CSC(C)=O)C[C@@]2(C)[C@@H](C)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([C@@H]2CN(C(=O)CSC(C)=O)C[C@@]2(C)[C@@H](C)O)cc1OCC1CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To a flask containing anhydrous K2CO3 (52 mg, 0.37 mmol, 4.0 eq) under a nitrogen atmosphere was added a solution of Example 118 (34 mg, 0.093 mmol, 1 eq) in anhydrous DMF (1 mL). Cyclopropylmethyl bromide (40 μL, 0.37 mmol, 4.0 eq) was added via syringe to the mixture. The slurry was stirred at 65° C. overnight. The reaction was cooled to room temperature, then diluted with water (50 mL). The aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic layers were washed with brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The resulting oil was purified by preparative TLC plate (100% EtOAc), yielding a clear, colorless oil (13.9 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[CH:27](O)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][N:24]([CH:27]=[O:28])[CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: O=CO
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCN(C=O)CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (12.0 mg, 0.0307 mmol), formic acid (2.3 μL, 0.0615 mmol), TBTU (19.7 mg, 0.0615 mmol), DIPEA (26.8 μL, 0.154 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.3 Hz, 3 H), 2.36-2.58 (m, 2H), 3.63-3.80 (m, 2 H), 4.05-4.15 (m, 2 H), 5.26 (q, J=7.2 Hz, 1 H), 5.86-5.97 (m, 1 H), 7.18 (t, J=8.7 Hz, 1 H), 7.24-7.31 (m, 1 H), 7.32-7.54 (m, 2 H), 8.09-8.17 (m, 1 H), 8.22 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 418.04 (100) [MH+]. HPLC: tR=3.40 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[NH:1][CH2:2][C:3]([N:5]2[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@@H:6]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:4])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CN
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 20.7 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 34, but starting from 2.0 g of tert-butyl (2R,4R) 3-(2-aminoacetyl)-2-phenyl-4-thiazolidinecarboxylate and 1.6 g of 4-chloro-3-trifluoromethylphenyl isocyanate. The crude product obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in 20 cm3 of hexane, 0.7 g of tert-butyl (2R,4R)-3-{2-[3-(4-chloro-3-tri-fluoromethylphenyl)ureido]acetyl}-2-phenyl-4-thiazolidinecarboxylate is thus obtained in the form of an amorphous powder, ([α]D20 =+58.2°±1.3° (C=0.49%; CH3OH), [proton NMR (250 MHz, DMSO D6, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 130° C., characteristic chemical shifts at 130° C.: 1.53 (s, 9H, --C(CH3)3); 3.29 and 3.47 (2dd, J=12.5 and 6.5, 2H, S--CH2 --); 3.73 (broad, 1H, of N--COCH2 --N); 4.10 (dd, J=17.5 and 4, 1H, the other H of N--COCH2 --N); 5.0 (broad, 1H, N--CH--COO); 6.33 (broad, 1H, --NHCO--); 6.4 (s, 1H, S--CH--N); 7.2 to 7.8 (m, 7H, aromatic); 7.97 (bs, 1H, in position 2 on CO--NH--Ph); 8.98 (broad, 1H, --CO--NH--Ph), [infrared spectrum (KBr), characteristic bands in cm-1 : 3375, 2980, 2930, 2875, 1740, 1640, 1595, 1550, 1485, 1455, 1370, 1325, 1175, 1150, 895, 730, 695].
Reaction SMILES: COC1C=CC(CNC(C)C)=CC=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:26]([CH:36]2[CH2:38][CH2:37]2)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:18]2[N:19]([C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[N:20]=1>CO>[Cl:14][C:15]1[CH:16]=[C:17]([N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:18]2[N:19]([C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: COc1ccc(CNC(C)C)cc1
Solvent: CO
Product: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C(C)C)cc1

Procedure:
10A was prepared from a mixture of 1F and N-(4-methoxybenzyl)propan-2-amine following the procedure employed for the preparation of 1G. HPLC: Rt=4.27 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=356.1 [M+H]+.