Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:28][S:27][C:23]1[N:24]=[C:25]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[CH:26]=[CH:21][N:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: CSc1nccc(I)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of t-butyl (4-hydroxy-1-naphthyl)carbamate (5.0 g, 19.3 mmol), 4-iodo-2-methylthiopyrimidine (4.86 g, 19.3 mmol) and cesium carbonate (7.52 g, 23.1 mmol) in DMF (25 ml) is heated at 70° C. for 20 h. The resulting mixture is diluted with CH2Cl2 (50 ml), washed with water (25 ml×3), dried over Na2SO4 and concentrated. This residue is dissolved in minimum volume of EtOAc at 70° C. and then hexane (20 ml) is added. The resulting solution is left at room temperature overnight, filtered and washed with hexane to obtain t-butyl (4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)carbamate as a pink solid (4.2 g); Mp: 173-174° C.; 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9 H), 2.30 (s, 3H), 6.45 (d, J=5.7 Hz, 1H), 6.86 (s, 1H), 7.27 (d, J=8.1Hz, 1H), 7.47-7.60 (m, 2H), 7.87-7.94 (m, 3H), 8.32 (d, J=5.7 Hz, 1H); MS: 384 (M+1).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cccc(F)c1F
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1cccc(F)c1F
Yield: 91 %

Procedure:
Prepared in 91% yield from 2-chloronicotinonitrile and 2,3-difluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 216.9 (M+H)+; 1H NMR (CDCl3) δ 7.21-7.29 (m, 1H), 7.30-7.39 (m, 2H), 7.49 (dd, J=8.0, 4.9 Hz, 1H), 8.12 (dd, J=7.8, 1.7 Hz, 1H), 8.92 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:22])[CH2:13]1>ClCCl>[O:9]=[S:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:22])[CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CSc2ccccc2N1
Solvent: ClCCl
Product: O=C1CS(=O)c2ccccc2N1
Temperature: 0 °C

Procedure:
A solution of 3-chloroperbenzoic acid (1.35 g, 6.6 mmol) in dry dichloromethane (40 ml) was added dropwise to an ice cooled solution of 2H-1,4-benzothiazin-3(4H)-one (1.10 g, 6.6 mmol) in dry dichloromethane (100 ml) with stirring. The reaction mixture was allowed to reach room temperature, then stirred overnight. The product was collected by filtration and washed with dichloromethane. Yield 0.54 g (45%) mp 184–6° C.
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([CH3:16])[O:15][C:3]=12.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:24]([CH3:39])[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=1>>[ClH:17].[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][S:22][C:23]3[N:24]([CH3:39])[C:25]([C:28]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:29]=4[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]5)=[N:26][N:27]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([CH3:16])[O:15][C:3]=12
Reactant: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Reactant: Cc1nc2cc3c(c(Br)c2o1)CCNCC3
Product: Cc1ccc2c(-c3nnc(SCCCCN4CCc5cc6nc(C)oc6c(Br)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 10-bromo-2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (100 mg) and 5-{5-[(4-chlorobutyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (177 mg) and was obtained as a colourless slightly hygroscopic solid (127 mg).
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br[CH2:11][CH2:12][CH2:13][CH3:14].[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[S:32][CH:33]=[CH:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1>CN(C)C=O>[CH2:11]([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[S:32][CH:33]=[CH:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2sccc2C1=O
Reactant: CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2ccsc2-3)no1
Reaction time: 1 h
Yield: 24.6 %

Procedure:
1.85 ml (10.9 mmol) of N-ethyldiisopropylamine and 0.7 ml (6.3 mmol) of 1-bromobutane were added to a solution of 1.0 g (3.16 mmol) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one in 30 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 290 mg (25%) of 7-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one as a colourless foam, Rf=0.37 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Br.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH2:23].C(N(CC)CC)C>CN(C)C=O>[BrH:1].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([OH:27])=[C:19]([OH:18])[CH:20]=1
Reactant: NCc1ccc(O)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1ccc(O)c(O)c1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 195.7 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (846 mg, 3 mmol) in N,N-dimethylformamide (7.5 mL) is added 3,4-dihydroxy benzylamine hydrobromide (660 mg, 3 mmol) and triethylamine (630 μL, 4.5 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.38 g of 6-Bromo-4-[(3,4-dihydroxy-benzylamino)-methylene]-4H-isoquinoline-1,3-dione hydrobromide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=O)[C:15]2=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC(OCC)=O.C[Si](C)(C)[O:46][NH2:47]>O1CCCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([NH:47][OH:46])=[O:22])[C:15]2=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(C)C(C(=O)O)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(C(=O)NO)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
2-(3-(4-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (50 mg; 0.13 mmol) was dissolved in tetrahydrofuran (THF; 2 ml). At 0° C., diisopropylethylamine (DIEA; 69 μl; 0.39 mmol) and ethyl chloroformate (25 μl; 0.26 mmol) were successively added. The mixture was allowed to reach RT from 0° C. over the course of 2 h, and then O-trimethylsilylhydroxylamine (50 μl; 0.65 mmol) was added. Stirring at RT for a further 3 h was followed by partitioning between dilute HCl (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3×; 5 ml). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. Trituration of the residue with EtOAc (2 ml) resulted in 2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyramide (25 mg; 0.06 mmol). MS: 398.15 (M+H); Rt: 1.30 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% 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: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][NH2:12].C(O[C:16](OCC)(OCC)[CH2:17][CH3:18])C.CC1C=CC(S(O)(=O)=O)=CC=1>[OH-].[Na+]>[CH2:17]([C:16]1[N:12]([CH3:11])[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1)[CH3:18]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1ccccc1C(=O)O
Reactant: CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc2ccccc2c(=O)n1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
A mixture of anthranilic acid (13.7 g, 100 mmol), methylamine (2M solution in methanol, 100 mL, 200 mmol), triethylorthopropionate (40 mL, 200 mmol), pTSA (catalytic amount) was heated at 70° C. with stirring for 3 days. The reaction mixture was cooled to room temperature, IN NaOH solution (160 mL) was added and the mixture stirred vigourously. The resulting precipitate was filtered, washed with water and dried under high vacuum to yield the product as a fluffy white solid (13.67 g, 73%). 1H NMR (400 MHz, CDCl3) δ 1.41 (t, 3H, J=7.4 Hz), 2.87 (q, 2H, J=7.4 Hz), 3.64 (s, 3H), 7.44 (t, 1H, J=8.1 Hz), 7.65 (dd, 1H, J=8.8, 0.7 Hz), 7.72 (t, 1H, J=8.4 Hz), 8.27 (dd, 1H, J=9.2, 1.8 Hz); ESI-MS m/z 189.0 (M+1)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[Cl:7][C:8]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:9]=1[CH2:10][NH:11][C:12]([NH:14][NH2:15])=[S:13].OS(O)(=O)=O.[CH3:26]O>>[Cl:7][C:8]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:9]=1[CH2:10][NH:11][C:12]([NH:14][N:15]=[C:2]([CH3:4])[C:1]([O:6][CH3:26])=[O:5])=[S:13]
Reactant: CC(=O)C(=O)O
Reactant: CO
Reactant: NNC(=S)NCc1cc(F)ccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)=NNC(=S)NCc1cc(F)ccc1Cl

Procedure:
To a solution of pyruvic acid (5.63 g, 64.0 mmol) in methanol (150 mL) was added N-(2-chloro-5-fluorobenzyl)hydrazinecarbothioamide (27, 14.9 g, 64.0 mmol) followed by cone. H2SO4 (3 mL) The mixture was heated at reflux for 15 h. Most of the solvent was evaporated. The resulting residue was taken into EtOAc (500 mL), washed with water, saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give methyl 2-(2-(2-chloro-5-fluorobenzylcarbamothioyl)hydrazono)propanoate (28). MS: m/z, 318 (100%, M+1), 320 (35%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[I:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][C:41](=O)[NH:40][N:39]=3)[CH:36]=2)[N:31]([S:44]([C:47]2[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH:30]=1.[C:54]1([C:60]([NH2:63])([CH3:62])[CH3:61])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[I:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][C:41]([NH:63][C:60]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([CH3:62])[CH3:61])=[N:40][N:39]=3)[CH:36]=2)[N:31]([S:44]([C:47]2[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=2)(=[O:45])=[O:46])[CH:30]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.5 %

Procedure:
BOP (455 mg, 1.029 mmol) was added to a stirred mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (450 mg, 0.935 mmol), 2-phenylpropan-2-amine (0.442 mL, 3.27 mmol) and diisopropylethylamine (0.33 mL, 1.87 mmol) in DMF (5.0 mL). The mixture was stirred at RT for 14 h. It was treated with BOP (300 mg) and 2-phenylpropan-2-amine (0.3 mL) and heated to 65° C. for 3 h. The mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification (eluting with 20-70% EtOAc in Hex) afforded 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-amine (103.6 mg, 19%) as a white amorphous solid. MS (ESI, pos. ion) m/z: 601.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[C:6]([NH2:15])[CH:5]=1.[C:17](Cl)(Cl)=[O:18]>ClCCl.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:17](=[O:18])[NH:15][C:6]=2[CH:5]=1)=[O:16]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(NC2CCC2)c(N)c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Reaction time: 2 h

Procedure:
To a solution of 3-amino-4-cyclobutylamino-benzoic acid methyl ester (15.94 g, 72.3 mmol) in dichloromethane (250 ml) at 23 C was added phosgene (38.3 ml of a 20% solution in toluene) dropwise over 30 minutes. The reaction was allowed to stand for 2 hours then was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 17.01 g of 1-cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](N)=[O:10])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[C:14](N)=[O:15].[OH2:17].S(=O)(=O)(O)[OH:19]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([OH:10])=[O:17])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[C:14]([OH:15])=[O:19]
Reactant: O
Reactant: NC(=O)c1c(Cl)c(Cl)c(C(N)=O)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)c1c(Cl)c(Cl)c(C(=O)O)c(Cl)c1Cl
Reaction time: 6 h

Procedure:
6.04 g (0.02 mol) of 2,3,5,6-tetrachloro-1, 4-benzenedicarboxamide and 17.65 g of sulfuric acid, consisting of 12.43 g of 96.3% sulfuric acid (containing 0.0256 mol of water) and 5.22 g of 26% fuming sulfuric acid (containing 0.017 mol of SO3), were charged into a reactor, and a hydrolysis of 2,3,5,6-tetrachloro-1,4-benzenedicarboxamide was performed at 180° C. for 6 hr under atmospheric pressure. The amount of water which was present prior to the reaction was 0.0086 mol because the SO3 in fuming sulfuric acid and the water in sulfuric acid were converted to sulfuric acid according to the formula (IV). After the completion of the reaction, precipitated crystals were collected by filtration, washed with water, and dried. As a result, 2,3,5,6-tetrachloro-1,4-benzenedicarboxylic acid was obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([CH3:21])[CH2:10][N:9]1[C:22](OC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CCOC(C)=O>C(Cl)Cl>[CH2:14]([N:12]1[C@@H:11]([CH3:21])[CH2:10][N:9]2[C:22](=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][C@@H:8]2[CH2:13]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1Cc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1CN2C(=O)c3ccccc3C[C@@H]2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A mixture of (2S,5R)-methyl 2,4-dibenzyl-5-methylpiperazine-1-carboxylate (0.28 g, 0.83 mmol), phosphorous oxychloride (5.0 ml) and phosphorous pentoxide (0.48 g, 1.6 mmol) was stirred at 100° C. under nitrogen overnight. The reaction was removed from the heat, quenched with ice, and brought to pH 7 to 8 with 1 N NaOH. Extraction with EtOAc (3×) and washing the combined organic layers with brine and drying over MgSO4 afforded 0.11 g of crude product after evaporation of the solvent. Flash chromatography (SiO2, CH2Cl2 to 60% EtOAc in CH2Cl2) afforded pure product (47 mg, 19% yield). MS (ESI) 307 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]1([CH:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C@@H:29]2[CH2:34][CH2:33][C@H:32]([N:8]3[CH2:12][CH2:11][CH:10]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH2:9]3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN([C@H]2CC[C@@H](c3ccccc3)CC2)C1

Procedure:
The title compound, MS: m/e=386.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and 4-phenylcyclohexanone.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([OH:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][CH2:17][CH3:18])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Br)ccc1C#N
Temperature: 60 °C
Yield: 100.9 %

Procedure:
A mixture of 4-Bromo-2-fluoro-benzonitrile (5 g, 25.00 mmol), potassium carbonate (10.37 g, 75.0 mmol), ethanol (6.86 mL, 117 mmol) in DMF (50 mL) was heated at 60° C. for overynight. After filtration and concentration, the residue was dissolved in ethyl acetate (150 mL), and the solution was washed with water (30 mL) and brine (50 mL). After drying over Na2SO4, filtration and concentration, a light brown solid (5.7 g) was obtained without further purification. 1H NMR (400 MHz, CDCl3): δ 1.49 (t, J=7 Hz, 3H), 4.14 (q, J=7 Hz, 2H), 7.11 (d, J=1.7 Hz, 1H), 7.14 (dd, J=8.1, 1.7 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]([C@H:6]2[CH2:11][CH2:10][C@H:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]4[N:37]=[CH:38][N:39]=[C:13]34)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1.C([Sn](=O)CCCC)CCC.[N:50]([Si](C)(C)C)=[N+:51]=[N-:52].C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]([C@H:6]2[CH2:11][CH2:10][C@H:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:52][N:51]=[N:50][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]4[N:37]=[CH:38][N:39]=[C:13]34)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.35 g), dibutyltin oxide (0.051 g), azidotrimethylsilane (2.3 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 46%).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](Cl)=[C:11]([C:16]2[C:17](Cl)=[N:18][S:19][N:20]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[SH2:23].[Na].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]2[S:23][C:17]3[C:16](=[N:20][S:19][N:18]=3)[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(Cl)=C(c2nsnc2Cl)C1
Reactant: S
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCc2sc3nsnc3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-benzoyl-4-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine (3.4 g, 10 mmol) in dimethylformamide was added sodiumhydrogensulfide monohydrate (1.5 g, 20 mmol) and potassium carbonate (2.0 g). The reaction mixture was stirred at room temperature for 3 h. Water (500 ml) was added and the water phase was extracted with diethylether (2×15 ml). The organic extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography, eluent: methylene chloride/ethyl acetate: 10/1, giving the title compound in 2.1 g yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.[N:27]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(OP(C#N)(=O)OCC)C.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:30]3[CH2:31][CH2:32][CH2:33][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:29]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)O)cc4)cnc3N)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)[nH]c2c1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]benzoic acid (108 mg, 0.3127 mmol) in DMSO (1 mL) were added tert-butyl 1,4-diazepane-1-carboxylate (187.9 mg, 0.9381 mmol), diethylcyanophosphonate (124.7 mg, 114.3 μL, 0.6879 mmol) and DIPEA (121.2 mg, 163.3 μL, 0.9381 mmol). The reaction mixture was heated at 80° C. overnight, allowed to cool and filtered and the resultant taken on to the next step without further purification (122 mg, 75% Yield).
Reaction SMILES: [NH:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([O:11]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].[ClH:23].[NH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][C:31](=[O:33])[N:30]([CH:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:35]([O:37][CH3:38])=[O:36])[C:29]1=[O:45].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C)C=O>[ClH:23].[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:32][C:31](=[O:33])[N:30]([CH:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:35]([O:37][CH3:38])=[O:36])[C:29]2=[O:45])=[O:11])=[CH:21][CH:22]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCN)C1=O
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCNC(=O)c2ccc(NC(=N)N)cc2)C1=O

Procedure:
384 mg (1.14 mmol) of 4-nitrophenyl 4-guanidinobenzoate, 390 mg (1.14 mmol) of methyl (3-(3-aminopropyl)-2,5-dioxoimidazolidin-1-yl)phenylacetate hydrochloride, 55 mg (0.4 mmol) of HOBt and 140 mg (1.2 mmol) of N-ethylmorpholine are stirred at room temperature for 5 h in 10 ml of dimethylformamide. Following concentration, chromatography takes place, for purification, on silica gel using a mixture of methylene chloride, methanol, glacial acetic acid and water=85:15:2:2. The fractions containing the pure substance are concentrated and freeze dried.