Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]2[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]2=[O:34])[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]5[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]5=[O:34])[CH:23]=[CH:24][CH:25]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(O)nn23)cn1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(C5C(=O)N(C)CCN5C)c4)nn23)cn1

Procedure:
3-{3-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a brown foam (56 mg, 42%). LCMS (m/e) 444 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.80-8.74 (m, 1H), 8.69 (s, 1H), 8.43 (dd, 1H, J=2.2 and 8.7 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.51 (s, 1H), 7.35-7.27 (m, 1H), 7.06 (d, 1H, J=7.6 Hz), 6.96-6.89 (m, 2H), 6.87 (d, 1H, J=8.7 Hz), 6.82 (d, 1H, J=4.78 Hz), 4.01 (s, 3H), 3.75-3.63 (m, 2H), 3.25-3.16 (m, 1H), 3.07-2.96 (m, 1H), 2.98 (s, 3H), 2.74-2.63 (m, 1H), 2.21 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[NH2:2].[Cl:21][CH2:22][C:23](=O)[CH2:24][Cl:25]>O1CCCC1>[Cl:21][CH2:22][C:23](=[N:2][NH:1][C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH2:24][Cl:25]
Reactant: O=C(CCl)CCl
Reactant: NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1
Solvent: C1CCOC1
Product: ClCC(CCl)=NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,3-dichloropropanone under nitrogen to give 2-[[2-chloro-1-(chloromethyl)ethylidene]-hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: Br.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.O1CCCC1.[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[CH2:20]([O:19][C:18]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:10]1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1ccc2c(c1)CNCC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
7-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (3 g) was dissolved in 1N aqueous sodium hydroxide solution (46 ml) and tetrahydrofuran (10 ml) and benzyl chlorocarbonate (2.45 g) was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with chloroform and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (3.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[N:14][CH:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:7][C:6]=2[CH:30]=1.[NH2:31][CH2:32][CH2:33][N:34]([CH3:43])[CH2:35][CH2:36][CH2:37][N:38]([CH2:40][CH2:41][NH2:42])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[N:14][CH:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8]([NH:42][CH2:41][CH2:40][N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH2:33][CH2:32][NH:31][C:8]3[C:9]4[C:10](=[O:18])[C:11]5[CH:12]=[CH:13][N:14]=[CH:15][C:16]=5[C:17]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][C:6]=4[N:7]=3)[CH3:43])[CH3:39])=[N:7][C:6]=2[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3cc(Cl)ccc3c3c2C(=O)c2ccncc2-3)cc1
Reactant: CN(CCN)CCCN(C)CCN
Product: CN(CCCN(C)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1ccncc1-2)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1ccncc1-2

Procedure:
In a similar manner to Example 4, this compound was obtained starting from toluene-4-sulfonic acid 3-chloro-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (the compound of Reference Example 7c-1) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([CH2:6][C@H:7]([CH3:18])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])(=[O:5])=[O:4]>C(O)(=O)C.[Pd]>[CH3:19][N:2]([CH3:1])[S:3]([CH2:6][C@H:7]([CH3:18])[C:8]([OH:10])=[O:9])(=[O:4])=[O:5]
Reactant: C[C@@H](CS(=O)(=O)N(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](CS(=O)(=O)N(C)C)C(=O)O
Reaction time: 24 h
Yield: 94 %

Procedure:
A 100 mL Fisher/Porter vessel was charged with 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate in 30 mL acetic acid with a catalytic amount of 10% Pd-C. The reaction was hydrogenated at 50 psi for 24 hours, filtered through Celite and concentrated in vacuo. The residue was azeotroped with toluene then concentrated in vacuo to afford 900 mg of 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionic acid which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][N:13]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([C:14]([NH2:16])=[O:15])[CH:10]=2)=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: NC(=O)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cc(C(N)=O)n[nH]4)n3)cc2CC1

Procedure:
The title compound was prepared from 5-(2,5-dichloropyrimidin-4-ylamino)-2H-pyrazole-3-carboxylic acid amide (70 mg, 0.2 mmol) and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (57 mg, 0.256 mmol) in an analogous manner to Example 946 to afford a tan solid (66 mg, 60%). Mp: 208-10° C. LCMS (m/e) 457 (M+1); 1H-NMR (d6-dmso, 400 MHz) δ 10.08 (s, 1H), 9.73 (m, 1H), 9.49 (s, 1H), 8.63 (br s, 1H), 8.15 (s, 1H), 7.80 (br s, 1H), 7.52 (m, 3H), 7.16 (d, J=8 Hz, 1H), 3.70 (m, 6H), 3.40 (m, 2H), 3.36 (s, 3H), 3.27-2.90 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: NC1CCCC1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Product: COc1ccc(NC(=O)NC2CCCC2)c([N+](=O)[O-])c1
Yield: 91 %

Procedure:
Phenyl 4-methoxy-2-nitrophenylcarbamate (1.1 g) and cyclopentylamine (0.37 g) were dissolved in xylene (10 ml) and the solution was heated under reflux for 2 hrs. After allowing the reaction solution to cool, the crystals formed was filtered, washed with xylene, and dried to give 1-(4-methoxy-2-nitrophenyl)-3-cyclopentylurea (0.97 g, 87%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl.[NH2:27][NH:28][C:29]([NH2:31])=[O:30].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20](/[C:23](=[N:27]/[NH:28][C:29]([NH2:31])=[O:30])/[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 1-(3-(1-(7-fluoroquinolin-6-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (60 mg, 0.18 mmol) in methanol (10 ml) was added semicarbazide hydrochloride (40 mg, 0.36 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 38 mg (yield: 54%) title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 8.84 (d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 7.96 (d, 1H), 7.77 (m, 3H), 7.44 (q, 1H), 6.69 (b, 2H), 5.03 (t, 1H), 2.07 (s, 3H), 1.83 (d, 3H). LCMS (method A): [MH]+=392, tR=4.88 min.
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.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38](O)=[S:39])=[C:32]2[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[NH2:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1.C(N(CC)CC)C>CN(C)C=O>[N:51]1[CH:52]=[CH:53][CH:54]=[C:49]([CH2:48][NH:47][C:38]([C:33]2[NH:34][C:35]3[C:31]([C:32]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:30][C:29]([Cl:28])=[CH:37][CH:36]=3)=[S:39])[CH:50]=1
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: S=C(NCc1cccnc1)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (0.73 g, 1.6 mmol) was added to a solution of 5-chloro-3-phenylthio-indole-2-carboxylic acid (0.50 g, 1.6 mmol), 3-aminomethylpyridine (0.35 g, 3.2 mmol) and triethylamine (0.50 mL, 3.2 mmol) in degassed dimethylformamide (25 mL). The reaction was stirred at room temperature overnight. The precipitated product was filtered and the filter cake washed well with water. The solid was triturated with 30% ethyl acetate in hexane, filtered and dried at 60° C. in vacuo for 72 h. The title compound was obtained as an off-white solid, mp 240°-241° C. Anal. Calc. for C21H16ClN3OS.0.25 H2O: C, 63.31; H, 4.17; N, 10.54. Found: C, 63.34; H, 4.06; N, 10.71. NMR (DMSO-d6): δ12.54 (1H, s), 8.91 (1H, t, J=6 Hz), 8.51 (1H, s), 8.42 (1H, d, J=5 Hz), 7.58 (2H, m), 7.45 (1H, m), 7.25 (4H, m), 7.15 (1H, t, J=7 Hz), 7.04 (2H, d, J=8 Hz), 4.58 (2H, d, J=6 Hz).
Reaction SMILES: [N+]([C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-])=O.[H][H]>[Pd].CO>[C:9]1([CH:4]([CH2:5][OH:6])[CH2:7][OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])C(CO)(CO)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCC(CO)c1ccccc1

Procedure:
12 g. (0.06 mole) of 2-nitro-2-phenyl-1,3-propanediol, 400 mg. of 5% palladium on calcium carbonate and 150 ml. of methanol are placed in a Parr hydrogenator bottle and reduced with hydrogen overnight. The mixture is filtered through Celite, concentrated to an oil and recrystallized from 30 ml. of toluene. The yield is 7.4 g. (80%) of product, M.P. 52°-4° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13]C(O)=O>CO.[Pd]>[CH3:1][N:2]1[C:3]2[C:4]([OH:12])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[CH:13]1
Reactant: CC(=O)O
Reactant: CNc1c(O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cn1cnc2cccc(O)c21

Procedure:
2-Methylamino-3-nitrophenol (1.00 g, 5.98 mmol) in MeOH (100 mL) with HOAc (0.22 mL) was hydrogenated (50 psi) for 2 hours over 10% Pd on carbon (186 mg). The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in formic acid and refluxed for 17 hours under N2 (g). Excess acid was removed in vacuo, and the residue was taken up in 5% MeOH in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was taken up in 5% MeOH in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to yield a red-brown solid which was chromatographed on silica (50-100% EtOAc/hexanes). The desired product (GC/MS m/z 148) was obtained as a yellow solid, 0.748 g; 84%.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:46][O:47][C:48](=[O:55])/[CH:49]=[C:50](\[CH3:54])/[CH2:51][CH2:52]O>C(OCC)(=O)C.C1COCC1>[CH3:46][O:47][C:48](=[O:55])/[CH:49]=[C:50](\[CH3:54])/[CH2:51][CH2:52][S:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: COC(=O)/C=C(\C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
5-Mercapto-1-phenyltetrazole (2.62 g, 14.60 mmol), triphenylphosphine (3.83 g, 14.60 mmol) and diisopropyl azodicarboxylate (95%, 2.96 g, 14.60 mmol) were added to a THF (36.8 ml) solution of methyl-(2E)-5-hydroxy-3-methylpent-2-enoate (1.16 g, 7.31 mmol) while ice cooling. The reaction solution was warmed to room temperature and stirred for two hours. After the reaction solution was diluted with ethyl acetate, it was washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=5:1) to obtain the title compound (2.33 g) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6](#[N:9])[CH:7]=[CH2:8]>>[N:1]1([CH2:8][CH2:7][C:6]#[N:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C=CC#N
Reactant: c1nc[nH]n1
Product: N#CCCn1cncn1
Temperature: 80 °C

Procedure:
A mixture of 1,2,4-triazole (25 g, 0.362 mol) and acrylonitrile (100 mL, 4 w/v) was heated up to 80° C. under nitrogen for 16 h. The reaction mixture was then concentrated under reduced pressure to remove the excess of acrylonitrile affording 41 g of the title compound as a colourless liquid (93%). It was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)cc(Cl)c2n1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CCN(Cc3cn4cc(Cl)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-α]pyridine (0.3064 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.266 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 1 h at 80-85° C. After cooling, the mixture is partitioned between water and dichloromethane and the organic layers are washed with brine and dried over MgSO4. After concentration under reduced pressure, the residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and the appropriate fractions are combined and concentrated and the residue is crystallized from ethyl acetate/hexane to give 0.3098 g of the title compound; mp 126.5-127.5° C.; MS m/z 378, 380; IR (mineral oil) 1510, 1215, 1335, 826, 1224 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.15, 3.83, 6.87, 6.96, 7.26, 7.62, 8.09.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([C:17]([O:19]CC)=[O:18])=[CH:11]3)=[CH:4][C:3]=1[O:22][CH2:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].O.[OH-].[Li+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([C:17]([OH:19])=[O:18])=[CH:11]3)=[CH:4][C:3]=1[O:22][CH2:23][C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CCOC(=O)c1cc2cc(-c3cnc(N)c(OCc4c(Cl)cccc4Cl)c3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ncc(-c2ccc3[nH]c(C(=O)O)cc3c2)cc1OCc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
To a mixture of ethyl 5-{6-amino-5-[(2,6-dichlorobenzyl)oxy]pyridin-3-yl}-1H-indole-2-carboxylate (2.5 g, 5.5 mmol) in methanol:water (60 mL:20 mL), lithium hydroxide (0.65 g, 27.1 mmol) was added. The reaction was heated to reflux for overnight. Most of the solvent was evaporated and the mixture was acidified, and stirred for 10 min. The precipitate was filtered out and washed with water to yield 5-{6-amino-5-[(2,6-dichlorobenzyl)oxy]pyridin-3-yl}-1H-indole-2-carboxylic acid as tan solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:9]=C[C:11]([F:17])=[C:12]([CH:16]=1)C(O)=O>ClCCl.CN(C)C=O>[Br:7][C:8]1[CH:16]=[CH:12][C:11]([F:17])=[C:1]([CH:9]=1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a well stirred suspension of 5-bromo-2-fluoro-benzoic acid (25.0 g, 114 mmol) in dichloromethane (150 mL) and N,N-dimethylformamide (1.5 mL) at 0° C. The resulting mixture was allowed to gradually warm to room temperature. After 18 hours, the solid had gone into solution. The resulting light orange solution was concentrated under reduced pressure and was chased two times with diethyl ether to afford 5-bromo-2-fluoro-benzoyl chloride (27.0 g, quantitative yield) as a pale orange oil.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[CH:14](O)=O>[Zn]>[S:1]1[C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N:11]=[CH:14]1
Reactant: O=CO
Reactant: O=C(O)c1ccc(S)c([N+](=O)[O-])c1
Agent: [Zn]
Product: O=C(O)c1ccc2scnc2c1
Temperature: 25 °C

Procedure:
A mixture of 4-mercapto-3-nitrobenzoic acid (1 eq.) and zinc dust (0.35 eq) in formic acid was refluxed for 6 h. The mixture was allowed to cool to room temperature, filtered and concentrated under reduced pressure. The residue was diluted with water, adjusted to pH=6.5 with aqueous NaOH (2N) and extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 95/5) to afford benzothiazole-5-carboxylic acid.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[OH-].[Na+]>[C:8]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(N)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a cooled solution of 3-aminobutyric acid (13 g) in 2M NaOH (130 ml) is added benzoyl chloride (19.7 g) over the course of two hours. The mixture is allowed to warm to room temperature. Washing with diethyl ether, acidifying of the aqueous phase with 20% HCI, extraction with diethyl ether, drying over MgSO4, evaporation of the solvent and recrystallization in ether/hexane gives the title compound m.p. 150°-152° C. (compound 1.16, Table 1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NCCCCO
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCCCCO

Procedure:
5-(4-Hydroxy-butylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 4-amino-1-butanol. Mass spectrum (ES) MH+=409.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[NH2:26][N:27]1[CH2:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[CH2:29][C:28]1=[O:40]>C(O)(=O)C>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([CH:30]2[CH2:31][N:27]([N:26]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)[C:28](=[O:40])[CH2:29]2)[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cc1ccnc2ccccc12)c1ccccn1
Reactant: COc1cccc(C2CC(=O)N(N)C2)c1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COc1cccc(C2CC(=O)N(N=C(Cc3ccnc4ccccc34)c3ccccn3)C2)c1
Reaction time: 18 h

Procedure:
A solution of 1-pyridin-2-yl-2-quinolin-4-yl-ethanone, (0.25 g, 1 mmol) and pyridine (0.242 mL, 3 mmol) in acetic acid (2 mL) is added to 1-amino-4-(3-methoxy-phenyl)-pyrrolidin-2-one, (0.2 g, 1 mmol) at room temperature under nitrogen. The mixture is stirred 18 h and concentrated in vacuo. The residue is chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 0.25 g (57%), as a yellow foam.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[I:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc(I)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 68 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-iodobenzenesulfonyl chloride under the conditions used in example 2 giving 68% of the title compound.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH2:42]/[CH:43]=[CH:44]/B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:44]=[CH:43][CH2:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: OB(O)/C=C/Cc1ccccc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(C=CCc4ccccc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-3-phenyl-1-propen-1-ylboronic acid (49 mg, 0.3 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(3-phenyl-propenyl)-benzyl]-imidazol-1-yl}-phenyl)-1, 2,5-thiadiazolidine-3-one-1,1-dioxide.