Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5](=[O:14])[C:6]=1[N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:15][N:4]1[C:3](=[O:16])[C:2]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:41][CH:42]=2)=[C:6]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[C:5]1=[O:14]
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: CN1C(=O)C(Br)=C(N2CCC(=O)CC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(N2CCC(=O)CC2)C1=O
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a room temperature, stirred solution of 3-bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione (100 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was added 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (151 mg, 0.41 mol) under a N2 atmosphere. The reaction mixture was stirred for 30 minutes and then Na2CO3 (87 mg, 1.04 mmol), water (4 mL) and Pd(PPh3)4 (40 mg, 0.03 mmol) were added also under a N2 atmosphere. The resulting mixture was then refluxed for 16 h, diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc in hexanes to afford 1-methyl-3-(4-oxopiperidin-1-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (80 mg, 52%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.45 (d, J=7.4 Hz, 1H), 8.12 (t, J=7.2 Hz, 2H) 7.79 (t, J=7.2 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.18 (d, J=7.2 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.62-3.58 (m, 4H), 2.96-2.85 (m, 4H), 2.56 (s, 4H). MS: M+: m/z=441.6; M+H: m/z=442.7. HPLC: 97%, (Condition-B).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:6]5[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=5)[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-(methylthio)benzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 10.6 (s, 1H), 8.30 (d, 1H), 7.53 (m, 9H), 7.05 (d, 1H), 6.43 (s, 1H), 2.48 (s, 3H); LC-MS: 388 (MH+); HPLC RT: 6.07 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[CH3:21].[NH2:22][C:23]([NH2:25])=[O:24]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[NH:22][C:23](=[O:24])[N:25]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: NC(N)=O
Reactant: Cc1cc(C(=O)/C=C/c2cccc(C(=O)O)c2)ccc1O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 47.4 %

Procedure:
(E)-3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)benzoic acid (15.0 g, 53.0 mmol) and urea (16.0 g, 0.27 mol) was suspended in 200 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 150 mL of 2-propanol, filtered and washed with 50 mL of 2-propanol and then dried in the air. 8.1 g (48%) of the desired 3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid was obtained. 1H NMR (400 MHz, DMSO-d6): 10.40 (s, 1H), 8.60 (s, 1H), 8.35 (m, 1H), 8.18 (m, 1H), 8.00 (s, 1H), 7.90 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 6.95 (m, 1H), 2.18 (s, 3H). MS (EI) for C18H14N2O4: 323 (MH+).
Reaction SMILES: C.CCCCCCC[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][CH:16]=1.[CH2:18]1OC1>>[CH3:18][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:9]
Reactant: C1CO1
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: C
Product: C=C(C)c1ccccc1
Yield: 69 %

Procedure:
A pigment preparation consisting of 35% of carbon black (surface area, measured by the BET method, of 230 m2 /g), 5% of a reaction product of 1 mol of nonylphenol and 6 mols of ethylene oxide, 6% of a reaction product of 1 mol of nonylphenol and 10 mols of ethylene oxide and 54% of a copolymer obtained from 69% of α-methylstyrene and 31% of acrylonitrile is produced as follows:
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])=S>C(#N)C.CN(C)C=O>[C:2]([NH:3][C:16]([NH:15][CH2:14][CH2:13][S:12][CH2:11][C:10]1[NH:9][CH:8]=[N:7][C:6]=1[CH3:5])=[N:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])#[N:1]
Reactant: Cc1nc[nH]c1CSCCNC(=S)NCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCSCc1[nH]cnc1C
Reaction time: 24 h

Procedure:
Lead cyanamide (8.7 g.) was added to a solution of N,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea in acetonitrile (100 ml.) and dimethyl formamide (20 ml.) and the resultant suspension was heated under reflux with stirring for 24 hours. Additional lead cyanamide (8.7 g.) was added and heating was continued for hours. Following filtration and concentration, the residue was chromatographed on a column of silica gel, eluting with ethyl acetate-isopropyl alcohol (5:1). Recrystallization from isopropyl alcohol-isopropyl acetate afforded N-cyano-N',N"-bis-[2-((4-methyl-5-imidazolyl) methylthio)ethyl]guanidine (0.6 g.), m.p. 92°-95°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:9]([NH:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1)=[O:13])[CH3:10]
Reactant: Nc1ccc(N)cc1
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 1,4-diaminobenzene (4 g, 37 mmol), ethyl isocyanate (1 mL, 12.6 mmol) and potassium carbonate (8.72 g, 63 mmol) in THF (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned in 1N HCl solution (80 mL) and ethyl acetate (80 mL). The aqueous layer was extracted with ethyl acetate (4×80 mL). The combined organic layers was dried, evaporated, recrystallized from MeOH/CH2Cl2/hexanes to give 4-(ethylaminocarbonylamino)aniline (1.4 g, 62%) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:10][CH:11]([F:14])[CH2:12][OH:13].CC(C)([O-])C.[K+].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:13][CH2:12][CH:11]([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)ccc1Br
Reactant: OCC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(OCC(F)F)ccc1Br
Temperature: 70 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a mixture of 3,6-dibromo-2-methylpyridine (2.00 g, 7.97 mmol) and 2,2-difluoroethanol (981 mg, 12.0 mmol) in THF (100 mL) is added potassium tert-butoxide (1.34 g, 12.0 mmol), and the mixture is stirred at 70° C. for 12 hours. After cooling to room temperature, the resulting mixture is poured to water (200 mL). The aqueous layer is extracted with ethyl acetate (200 mL×2). The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (8:1) to give 1.94 g (97% yield) of the title compound as colorless oil.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27].[BH4-].[Na+].Cl>CO>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:27][CH2:26][CH2:25][NH2:28])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reactant: NCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCNCc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reaction time: 24 h

Procedure:
3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.3 mmol) was stirred for 24 hrs with the excess of ethylene diamine (1 mmol) in methanol. Sodium borohydride (0.6 mmol) was added and stirring continued for another 24 hrs. After completion, the volatiles were removed in vacuo, crude material diluted with cold water, acidified to pH 3.4, filtered off, washed on a filter with cold water and dried to afford the target material as a free base. The latter was converted into hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCl and the evacuation of the volatiles in vacuo to afford the title compound, mp>200° C.; MS (ES+) 381[M+H]+
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Na]>C(O)C>[CH:3]1([CH2:2][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCCCC1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CCO
Product: c1cn(CC2CCCCC2)cn1

Procedure:
Bromomethylcyclohexane (39.8 g; 0.225 mole) was added dropwise to a refluxing solution of imidazole (13.6 g; 0.2 mole) and sodium (4.6 g; 0.2 mole) in absolute ethanol (100 ml). After addition the reaction mixture was heated under reflux for a further 5 hours. After this period the mixture was cooled and the solvent evaporated under reduced pressure. The residue was taken up in water (150 ml), washed with ether (50 ml) and extracted with chloroform (3×50 ml). The combined chloroform extracts were dried over anhydrous magnesium sulphate and evaporated under reduced pressure to leave a residual yellow oil as crude product which was purified to give the product as a colourless oil b.p. 86°-90° C./0.2 mmHg. The product solidified on cooling, m.p. 25° to 30° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:19]=O)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1.[C:40]([CH2:42]P(=O)(OCC)OCC)#[N:41].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[CH:42][C:40]#[N:41])[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:3]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a stirred solution of (16) (335 mg, 0.611 mmol) and diethyl cyanomethylphosphonate (104 μl, 0.64 mmol) in THF (10 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (151 mg, 1.34 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 243 mg (70%) of a white foam; 1H NMR (200 MHz, CDCl3) δ 1.10 (6H, d, J=6.8 Hz), 2.32 (3H, s), 2.68 (1H, m), 3.78 (3H, s), 4.30 (2H, d, J=5.2 Hz), 4.68 (2H, s), 5.23 (1H, t, J=5.2 Hz), 5.82 (1H, d, J=16.6 Hz), 6.05 (1H, s), 6.21 (1H, s), 6.62 (2H, s), 6.84-6.90 (2H, m), 6.97 (1H, s), 7.18-7.27 (3H, m), 9.63 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.[N+:21]([C:24]1[N:25]=[C:26]2[N:31]([CH:32]=1)[CH2:30][C@H:29]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=1)[CH2:28][O:27]2)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:38]1[CH:37]=[N:36][C:35]([CH2:34][O:33][C@H:29]2[CH2:28][O:27][C:26]3=[N:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][N:31]3[CH2:30]2)=[CH:40][CH:39]=1
Reactant: CC1(C)OB(c2ccc(CO[C@@H]3COc4nc([N+](=O)[O-])cn4C3)nc2)OC1(C)C
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1O[C@H](Cn2ccnn2)CN1c1ccc(-c2ccc(CO[C@H]3COc4nc([N+](=O)[O-])cn4C3)nc2)c(F)c1
Temperature: 60 °C
Yield: 48.2 %

Procedure:
3-(3-Fluoro-4-iodo-phenyl)-5(R)-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (90 mg, 0.232 mmol), 2-Nitro-6(S)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (108 mg, 0.278 mmol), K2CO3 (244 mg, 0.464 mmol) and Pd(PPh3)4 (27 mg, 0.023 mmol) were combined and suspended in DMF (2 ml) and water (0.2 ml). The mixture was heated to 60° C. for 1½ hours then quenched with sat. aqueous NH4Cl (2 mL) at rt. The mixture was diluted with EtOAc (10 mL) and washed with water (5 mL×5). The organic phases were dried (MgSO4) and concentrated. Column chromatography (2% MeOH/CH2Cl2) provided 60 mg (50%) of the title product as yellow solid. LCMS (ESI) m/z 523 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[CH3:17][Sn:18]([CH3:20])([CH3:19])[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound from Step A (0.92 g, 4 mmol) in THF (25 mL) was added n-BuLi (2.5 M solution in hexane, 3.48 mL) dropwise at −78° C. After the addition, the reaction mixture was stirred at −78° C. for an additional 30 min. To this solution was added trimethyltin chloride (0.88 g, 4.4 mmol) in THF (8 mL) dropwise for a period of 10 min. The reaction mixture was brought to room temperature slowly and stirred at room temperature overnight. Saturated aqueous ammonium chloride (60 mL) was added and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified over silica gel to give the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.[N:51]1([CH2:57][CH2:58]O)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[N:51]1([CH2:57][CH2:58][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)[NH:11][C:9]([C:6]2[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)=[O:10])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: OCCN1CCOCC1
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCCN2CCOCC2)[nH]n1
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydr oxy-propionic acid (41.0 mg, 86 μmol), HOBt (70.0 mg, 518 μmol) and EDC (92 μL, 520 μmol) were combined in DCM (0.7 mL, 10 mmol). The resulting solution was stirred for 10 minutes. 4-Morpholineethanol (84 μL, 691 μmol) was added, and the mixture was stirred at room temperature until the reaction was complete (≈2 hours). The mixture was concentrated by rotary evaporation and purified (reverse phase column) to yield the title compound (7.5 mg, purity 98%) as a TFA salt. MS m/z [M+H]+calc'd for C28H31ClFN5O6, 588.19. found 588.1.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[O:16]1[C:15]2([CH2:14][CH2:13][CH:12]([N:25]3[CH:24]=[C:23]([I:22])[CH:27]=[N:26]3)[CH2:21][CH2:20]2)[O:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Ic1cn[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (prepared according to U.S. Pat. No. 4,360,531) (2.0 g, 6.4 mmol), 4-iodopyrazole (1.36 g, 7.0 mmol), K2CO3 (1.06 g, 7.7 mmol), and 18-crown-6 (0.2 g, 0.7 mmol) in DMF (5 mL) was heated under nitrogen at 50° C. for 16 h. Water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (3×40 mL). The combined EtOAc extracts were washed with water (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/CH2Cl2 (1:9) to give the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.67-1.76 (m, 2 H), 1.84-1.91 (m, 2 H), 1.99-2.17 (m, 4 H), 3.95-3.99 (m, 4 H), 4.18-4.27 (m, 1 H). MS (ES+): m/z=334.96 (100) [MH+]; HPLC: tR=3.26 min (polar—5 min, ZQ3).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]#[N:15].C(OP(=S)(OCC)[SH:20])C>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([NH2:15])=[S:20]
Reactant: N#CCCN1C(=O)c2ccccc2C1=O
Reactant: CCOP(=S)(S)OCC
Solvent: O
Product: NC(=S)CCN1C(=O)c2ccccc2C1=O
Yield: 91 %

Procedure:
A suspension of 3-(1,3-dioxoisoindolin-2-yl)-propionitrile (2 g, 9.99 mmol) and dithiophosphoric acid O,O′-diethyl ester (2.05 g, 1.74 mL, 11.0 mmol) in water (4 mL) was irradiated at 80° C. for 10 min. The obtained suspension was diluted with water (5 mL), filtered, washed with water and dried in vacuo to give the product as light yellow solid (2.13 g, 9.09 mmol, 91.0%) which was used without further purification for the next step. MS: M=235.1 (M+H)+
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[CH2:18]([S:22]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NC1Cc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NC1Cc2ccccc2C1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To 87.44 g of 2-aminoindane dissolved in 800 ml of methylene chloride was added 66.43 g of triethylamine, and 102.8 g of n-butylsulfonyl chloride was added dropwise thereto under ice cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with diluted hydrochloric acid and dried, and then the solvent was removed. The resulting crystals were recrystallized from isopropyl ether to obtain 151.12 g of 2-n-butylsulfonylaminoindane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[C:28]4[S:24][C:25](=[O:30])[NH:26][C:27]4=[O:29])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(-c2cccc(Oc3ccc(C=O)cc3)c2)cc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)c2)cc1
Yield: 77.5 %

Procedure:
A mixture of 57 (1.23 g, 4.0 mmol), 2,4-thiazolidinedione (0.48 g, 4.0 mmol), benzoic acid (0.60 g, 4.8 mmol) and piperidine (0.61 mL, 6.0 mmol) in toluene (30 mL) was heated to a vigorous reflux until most of the solvent had evaporated. A yellow suspension was achieved by addition of acetic acid (25 mL) followed by sonication. Filtration of the suspension followed by washing with acetic acid (10 mL) yielded 58 (1.25 g, 75%) after filtration and oven drying. 1H NMR (400 MHz, DMSO-d6): δ 12.57 (br s, 1H), 7.78 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.49 (d, J=5.2 Hz, 2H), 7.36 (t, J=1.6 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 3.7 (s, 3H).