Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:3][C:4]1[C:9]([O:10][C:11]2[C:16]([S:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[CH:25][S:26][C:19]=34)=[CH:15][N:14]=[C:13]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH:33]4[CH2:38][CH2:37][N:36]([C:46](=[O:48])[CH3:47])[CH2:35][CH2:34]4)[N:32]=3)[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1ncccc1Oc1cc(Nc2nc(C3CCNCC3)cs2)ncc1Sc1ccnc2ccsc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2csc(Nc3cc(Oc4cccnc4C)c(Sc4ccnc5ccsc45)cn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
4-(2-Methylpyridin-3-yloxy)-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride (0.051 g, 0.08 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (0.10 mL, 0.74 mmol) and acetic anhydride (0.017 mL, 0.19 mmol) were added and the reaction was stirred at ambient temperature overnight. Saturated sodium bicarbonate solution was added, and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (0.051 g, 70% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.50 (d, 1H), 8.41 (dd, 1H), 7.73 (d, 1H), 7.56 (d, 1H), 7.19 (m, 1H), 7.17 (m, 1H), 6.92 (d, 1H), 6.40 (d, 1H), 6.36 (s, 1H), 4.67 (m, 1H), 3.86 (m, 1H), 3.13 (m, 1H), 2.69 (m, 2H), 2.16 (s, 3H), 1.94 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>CCO>[NH:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[NH2:15]
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Reactant: NN
Solvent: CCO
Product: NNc1cnc2cc(Cl)c(Cl)cc2n1

Procedure:
To the 2,6,7-trichloroquinoxaline was added anhydrous EtOH (500 ml) to give a brown solution. 5.0 g (156 mmol) anhydrous hydrazine were added dropwise under N2, turning the solution red immediately. The solution was heated at reflux for 1 hour, cooled and the resulting solid was collected. Recrystallization from 1500 ml 95% EtOH yielded 13.0 g of 2-hydrazino-6,7-dichloroquinoxaline.
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][NH2:1]
Reactant: CN1CCNCC1CCCc1cccc2c1C(=O)NC2=O
Reactant: NN
Solvent: CO
Product: CN1CCNCC1CCCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 3-(N-methylpiperazinyl)propylphthalimide (229 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].B(O)(O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:22][CH:23]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2ncc(-c3ccncc3)cc2c1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
3-Bromo quinoline (0.2 g, 0.00096 mol) was dissolved in DMF:water (3:1, 4 mL). To this was added potassium phosphate (0.611 g, 0.00288 mol) and pyridyl-4-boronic acid (0.141 g, 0.00115 mol) at RT. The reaction mixture was degassed for 5 min, and to this was added Pd(PPh3)4 (0.055 g, 0.000048 mol). The reaction mixture was heated by microwave at 80° C. for 1.5 h. After completion of reaction (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, and the residue purified by column chromatography (45% ethylacetate:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound (0.13 g, 63% yield).
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>S(=O)(=O)(O)O.O>[C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])[NH2:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Temperature: 85 °C
Reaction time: 9 h

Procedure:
3-(R,S)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine (30 g-see Preparation 7) was dissolved in 95% sulphuric acid (210 ml) and the mixture was heated, with stirring, at 85° C. for 9 hours and then at 100° C. for 30 minutes. The mixture was allowed to cool to room temperature and poured onto ice (2 kg). The mixture was basified (pH 12) by addition, in portions with cooling in an ice bath, of a cold solution of sodium hydroxide (340 g) in water (500 ml). The resulting mixture was extracted with dichloromethane (3×300 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a foam, yield 16.4 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[F:23]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(O)c1ccccc1F
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2F)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 2-fluorobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-fluorobenzoamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 452.3 (M)+
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[C:29](O)(=[O:32])[CH2:30][OH:31].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:30](=[O:31])[CH2:29][OH:32])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: O=C(O)CO
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)CO)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (110 mg) in dimethylformamide (6 ml) were added, under argon, glycolic acid (19 mg), diisopropylethylamine (32 mg) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 159 mg). Then diisopropylethylamine (64 mg) was added once again to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-{3-[2-(1-glycoloylpiperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl methanesulphonate (15 mg, 12%).
Reaction SMILES: I[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[O:5][N:4]=1.[O-:18][CH2:19][CH3:20].[Na+]>>[CH2:19]([O:18][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[O:5][N:4]=1)[CH3:20]
Reactant: FC(F)(F)c1ccncc1-c1nc(CI)no1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOCc1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-Iodomethyl-5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole (0.5 g) was dissolved in a freshly prepared solution of sodium ethoxide (30 mg of sodium in 7 ml of ethanol), and the mixture was stirred at room temperature for 6 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: Sc1nc2ccccc2s1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3nc4ccccc4s3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-benzothiazole.
Reaction SMILES: F[C:2]([CH3:9])([CH3:8])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].C([O-])(O)=O.[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(OCC)(=O)C>[C:15]([NH:4][C:3](=[C:2]([CH3:9])[CH3:8])[C:5]([OH:7])=[O:6])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(F)C(N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)=C(NC(=O)c1ccccc1)C(=O)O
Reaction time: 4 h

Procedure:
To a suspension of 3-fluoro-DL-valine (165 mg, 1 mmol) in ethyl acetate (10 mL) was added NaHCO3 (sat. aq., 5 mL) followed by benzoyl chloride (1 mmol). The solution was stirred for 4 h, acidified with 1N HCl, and then extracted into ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated to provide the crude 2-benzamido-3-methylbut-2-enoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (60 mg, 0.3 mmol), 3-methyl-4-(piperidine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (75 mg, 0.34 mmol) and piperidine (0.14 mL) in ethanol (2 mL) was stirred at 100° C. overnight. The reaction was column chromatographed (2-3% methanol in dichloromethane) to give 20 mg (17%) of the title compound as a yellow orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:21]([NH:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:27]([O:45][CH3:46])[CH:26]=1)(=[O:23])[CH3:22]>CN(C)C=O>[C:21]([NH:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][CH2:31][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)=[C:27]([O:45][CH3:46])[CH:26]=1)(=[O:23])[CH3:22]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1cc(NC(C)=O)ccc1OCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NC(C)=O)ccc1OCCN1CCN(c2ccccc2F)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
1.07 g of 4-(2-fluorophenyl)piperazine and 1.5 ml of triethylamine are added to a solution of 1.5 g of 2-(4-acetamido-2-methoxyphenoxy)-1-(p-toluenesulfonyloxy)ethane in 10 ml of anhydrous dimethylformamide, and the mixture is stirred at 100° C. for 6 hours. After the reaction, the mixture is poured into ice-water, and the aqueous mixture is extracted with chloroform. The extract is washed with water and an aqueous saturated sodium chloride solution, successively. Said extract is dried and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (Solvent; 2% methoanol/chloroform), and then recrystallized from a mixture of ethyl acetate and n-hexane. 1.3 g of 1-[2-(4-acetamido-2-methoxyphenoxy)ethyl]-4-(2-fluorophenyl)-piperazine are thereby obtained as colorless scales. Yield: 85%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-methoxy-3-nitrobenzoic acid (10.0 g, 0.051 mol), and thionyl chloride (25 g, 0.212 mol), were refluxed together for 24 h. The reaction mixture was cooled to RT and concentrated to dryness. The off-white solid was carried onto the next step.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16](=[O:26])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1ccccc1-3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (7S)-14-cyclohexyl-7-hydroxy-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from Step 3) in DCM (0.1 M) was added Dess-Martin periodinane (DMP, 1.2 eq), and the mixture was stirred for 1 h at RT. At this point another 0.6 eq of DMP were added and the reaction left overnight. The reaction mixture was diluted with EtOAc and washed with an aqueous solution of a 1:1 mixture containing sodium thiosulfate and NaHCO3 (both saturated solutions), then with water and brine. Drying over Na2SO4, filtration and concentration in vacuo gave the crude product, which was used without further purification (90%); MS (ES+) m/z 404 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][C:5]=12.C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:27][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)c1cccc(-c2ccn3ccnc3c2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Imidazo[1,2-a]pyridine-7-yl-N-methyl-benzamide (1 eq, 0.398 mmol, 100 mg) is dissolved in DMF (4 ml) at 0° C. and NBS (1.1 eq, 0.438 mmol, 77.9 mg) is added. The reaction mixture is stirred for 1 h at 0° C. and then is diluted with EtOAc. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 3-(3-bromo-imidazo[1,2-a]pyridin-7-yl)-N-methyl-benzamide as a brown solid; [M+H]+=331
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH2:63][CH2:62][C@H:61]1[C:65](=[O:79])[NH:66][C:67]1[S:68][CH:69]=[C:70]([C:72]2[CH:77]=[CH:76][C:75]([NH2:78])=[CH:74][CH:73]=2)[N:71]=1)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH2:63][CH2:62][CH:61]1[C:65](=[O:79])[NH:66][C:67]1[S:68][CH:69]=[C:70]([C:72]2[CH:73]=[CH:74][C:75]([NH:78][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]3[CH:16]4[CH:11]([NH:12][C:13](=[O:14])[NH:15]4)[CH2:10][S:9]3)=[CH:76][CH:77]=2)[N:71]=1)=[O:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 mg (0.28 mmol) of biotin was dissolved in 5 mL of dry DMF. To this solution were added DIEA (0.34 mmol, 0.06 mL) and HATU (0.28 mmol, 0.1 g). This solution was stirred at room temperature for 2 hours. 80 mg (0.189 mmol) of Compound 5050 was then added to the reaction mixture and stirred at room temperature overnight. Reaction mixture was evaporated to dryness and redissolved in 5 mL of DMF and purified using reverse phase HPLC. MS: 649.2 (M+H+).
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][CH2:7]I.[CH:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13].C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O.C(Cl)Cl.CN(C)C=O>C(Cl)Cl>[OH:3][CH2:4][CH2:5][O:6][CH2:7][C:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13]
Reactant: C[Si](C)(C)OCCOCI
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The iodomethyl 2-(trimethylsilyloxy)ethyl ether solution prepared in example 2 was kept in a dry ice-acetone bath and a dry solution of nitroform (76 g; 0.5 moles) in 375 ml of methylene chloride was added over 20 minutes through an addition funnel. [See Example 5 for the preparation of the nitroform solution]. After the addition of the nitroform-methylene chloride solution was complete, dry dimethylformamide (100 ml) was added and after five minutes the reaction solution was removed from the dry ice-acetone bath and allowed to warm to near 0° C. (takes about 45 minutes). The solution was then cooled in an ice bath for 15 minutes before it was poured into 600 ml of ice water. The lower organic layer was separated after which the aqueous phase was extracted with 3×25 ml of methylene chloride. The combined organic extracts were dried over sodium sulfate and then allowed to stand in a hood in a current of air to remove volatiles. The residue (approximately 150 g but depends on the amount of dimethylformamide lost) contains mainly 2,2,2-trinitroethyl 2-hydroxyethyl ether1 and dimethylformamide along with much smaller amounts of two byproducts2 (A and B). The crude ether was added to 46 ml of concentrated hydrochloric acid and the mixture was stirred well at 60°-65° C. for 1 hour. After cooling to room temperature, 30 ml of methylene chloride was added and the organic layer was separated and washed with 3×30 ml of water. The combined water extracts (90 ml) were back extracted with methylene chloride (30 ml) and the combined organic extracts were dried over sodium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:32]2[CH2:33][CH2:34][CH:29]([CH2:28][N:25]3[CH2:26][CH2:27][N:22]([C:20]4[CH:19]=[CH:18][N:17]=[C:16]([CH3:15])[N:21]=4)[CH2:23][CH2:24]3)[CH2:30][CH2:31]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nccc(N2CCN(CC3CCNCC3)CC2)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCN(CC3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
A solution of 4-chlorophenylsulphonyl chloride (1.78 g) in methylene chloride (10 ml) was added dropwise over 15 minutes to a mixture of 4-[1-(2-methylpyrimidin-4-yl)piperazine-4-ylmethyl]piperidine trihydrochloride (2.78 g) and triethylamine (6.72 ml) in dichloromethane (40 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 4% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4ylmethyl]piperidine (2.50 g), mp 191-193° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]#[N:18]
Reactant: N#CCCl
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1ccccc1F
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a solution of 2-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 736 mg of the product 384.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=Cc1cccc(-n2cccn2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 406.12 g/mol.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([CH:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13]C)=[S:12])=[N:6][N:5]=[N:4]1>O>[CH3:2][N:3]1[C:7]([CH:8]([CH3:15])[CH2:9][CH2:10][C:11]([OH:13])=[S:12])=[N:6][N:5]=[N:4]1
Reactant: COC(=S)CCC(C)c1nnnn1C
Agent: Cl
Solvent: O
Product: CC(CCC(O)=S)c1nnnn1C

Procedure:
20% aqueous Hydrochloric acid (150 ml) is added to methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiovalerate (17 g) and the mixture is refluxed for 2 hours. After cooling, the reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeric acid, colorless liquid, nD26 =1.5133.