Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>CC(O)CC.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[CH:5][CH:4]=1
Reactant: C=CCn1c(=O)cnc2ccc(OC)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Product: COc1ccc2ncc(=O)n(CC=O)c2c1
Reaction time: 3.75 h
Yield: 65.6 %

Procedure:
A mixture of 7-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinoxalinone (1.03 g, 4.75 mmol) and sodium periodate (4.68 g, 21.8 mmol) in 2-butanol (20 mL) and water (40 mL) was treated with osmium tetroxide (4% solution in water, 1.1 mL) and the mixture was stirred for 3.75 h. The butanol was evaporated and the residue was diluted with water and extracted with dichloromethane, then with dichloromethane/THF. The extracts were dried and evaporated, and the residue was chromatographed on silica eluted with 50-100% ethyl acetate/hexane to give the aldehyde (0.68 g, 66%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(O)(=O)C.O>CCO>[N:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:2])=[CH:29][CH:30]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCc1ccncc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#Cc1nc(C(=O)NCc2ccncc2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Yield: 35.1 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (35 mg, 0.104 mmol) and 4-(aminomethyl)-pyridine (0.040 mL, 0.366 mmol) in 2 mL of EtOH was refluxed for 16 h. Acetic acid (0.1 mL) and water (3 mL) were added, and the mixture was allowed to come to r.t. The resulting precipitate was filtered, washed with 5 mL of water/MeOH (1:1), and dried under high vacuum to afford 15 mg of the title compound as a gray solid. MS: (+) m/z 412.20 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:19][CH:18]3[C:20](=[O:21])[CH:15]([CH2:16][CH2:17]3)[CH2:14][C:13]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:8][C:9]1[CH:22]=[C:13]2[C:12](=[CH:11][CH:10]=1)[CH2:19][CH:18]1[C:20](=[O:21])[CH:15]([CH2:16][CH2:17]1)[CH2:14]2)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)CC1CCC(C2)C1=O
Temperature: 90 °C
Yield: 80 %

Procedure:
Ethyl bromoacetate (8.01 g) was added to a stirred solution of [6S/R,9R/S]2-Hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-one (9.7 g; J. Org. Chem 1982, 47, 4329) and potassium carbonate (6.6 g) in dry DMF (150 mL). The reaction was warmed to 90° C. for 18 hours, cooled to room temperature, diluted with water (200 mL), and extracted into ether (4×100 mL). The organic extracts were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash chromatography over silica (200–400 mesh, 0–30% EtOAc/isoHexane) afforded (13-oxo-tricyclo[8.2.1.03,8]trideca-3,5,7-trien-5-yloxy)-acetic acid ethyl ester (11.07 g) 1H NMR (CDCl3 400 MHz) δ 1.28 (3H, m), 1.84 (2H, m), 2.58 (2H, m), 2.86 (4H, m), 4.15 (2H, m), 4.22 (2H, m), 4.59 (2H, s), 6.71 (1H, dd, J=8.0, 4.0 Hz), 6.80 (1H, d, J=4.0 Hz), 7.10 (1H, d, J=8.0 Hz).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N:22]1([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCNCC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCNCC2)c(-c2cccnc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-(1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 145.1, 51 mg, 0.111 mmol), pyridin-3-ylboronic acid (13.6 mg, 0.111 mmol), and Na2CO3 (35 mg, 0.333 mmol) in a mixture of DME (2.4 mL), EtOH (0.32 mL) and water (0.48 mL) was flushed with argon. Pd(PPh3)2Cl2 (4 mg, 0.005 mmol) was added and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.7 min, m/z=458.1 [M+H]+, m/z=456.2 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH3:54])=[N:51][C:50]=2[CH:55]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:54][C:52]1[O:53][C:49]2[CH:48]=[CH:47][C:46]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:19][CH:18]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:55][C:50]=2[N:51]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: Cc1nc2cc(OB([O-])[O-])ccc2o1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.35 g) was added toluene/ethanol/water (10/1/1,16.3 ml) and then were added 2-methyl-1,3-benzoxazol-5-yl borate (0.14 g) and potassium carbonate (0.23 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (31 mg), and the mixture was refluxed for 14 hours, cooled to room temperature, poured into water. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1) and recrystallized from ethanol to give 7-(2-methyl-1,3-benzoxazol-5-yl)-N-[4-([N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 135) (110 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:36][CH2:37][OH:38].C(OCC)(=O)C>C(#N)C>[CH2:23]([C@@H:19]1[N:20]([CH2:36][CH2:37][OH:38])[CH2:21][CH2:22][N:17]([C:15]2[N:16]=[C:11]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[NH:4][N:3]=[C:2]4[CH3:1])[N:12]=[N:13][CH:14]=2)[CH2:18]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1n[nH]c2ccc(-c3nncc(N4CCN[C@@H](Cc5ccccc5)C4)n3)cc12
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1n[nH]c2ccc(-c3nncc(N4CCN(CCO)[C@@H](Cc5ccccc5)C4)n3)cc12
Yield: 7.3 %

Procedure:
To a solution of 5-[(S)-3-benzylpiperazin-1-yl]-3-(3-methylindazol-5-yl)-[1,2,4]triazine 12 (28.5 mg, 0.074 mmol.) in acetonitrile (2 mL) was added sodium bicarbonate (6.2 mg, 0.074 mmol.) and 2-bromoethanol (9.2 mg, 0.11 mmol.). The reaction mixture was heated under gentle reflux overnight. Ethyl acetate (50 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 5-[(S)-3-benzyl-4-hydroxyethyl-piperazin-1-yl]-3-(3-methylindazol-5-yl)-[1,2,4]triazine 60 (2.3 mg, 0.0054 mmol.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>ClCCl>[N:28]([CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a stirred solution of Part A N-BoC-3-hydroxymethylpiperidine (27.0 g, 126 mmol) in 150 mL of dry dichloromethane under argon at 0° C. was added in order triethylamine (22.7 mL, 163 mmol) and methanesulfonyl chloride (11.7 mL, 151 mmol). The reaction was stirred at room temperature for 1.5 h and diluted with 450 mL of dichloromethane. The reaction was washed with 0° C. 1N HCl solution (2×100 mL) and brine (1×100 mL). The dichloromethane layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in 200 mL of DMF and combined with sodium azide (24.5 g, 377 mmol). The mixture was stirred at room temperature for 33 h and the solid was filtered off. The filtrate was concentrated under pump vacuum at 45° C. The residue was partitioned between 400 mL of EtOAc and 10% sodium thiosulfate solution (2×100 mL) and brine (1×100 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo. Purification was effected by a flash column chromatography on silica gel to give 19.5 g (65%) of title azide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>O.C(O)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:11][CH3:12])=[C:2]([Br:1])[CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N)cc1Br
Temperature: 25 °C

Procedure:
A mixture 2-bromo-4-nitroanisole (15 g, 64.6 mmol) and iron powder (27.3 g, 0.49M) in water (100 ml) and glacial acetic acid (25 ml) was stirred at reflux for 2h. The mixture was allowed to cool to ambient temperature and filtered through a pad of Hyflo™ (washed with 25% acetic acid/water). The filtrate was extracted with ethyl acetate (2×250 ml) and the organic layer was dried over sodium sulphate. Removal of the solvent in vacuo left an oil which was chromatographed on silica in 40% ethyl acetate/hexane giving the title compound as a brown solid (10.32 g, 79%). MS (ES+) 202 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:23])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:24]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[F:23][C:4]1[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:34][CH:35]=2)[CH:3]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCCCC)cc3)c(F)c2)cc1
Yield: 70 %

Procedure:
4.00 g (10.51 mmol) of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine, 2.63 g (10.51 mmol) of 4-octyloxybenzeneboronic acid, 0.12 g (0.11 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2.23 g (21.02 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 100 ml of toluene, 70 ml of ethanol and 40 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, and the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, evaporated and purified by chromatography (silica gel/dichloromethane), giving 3.72 g of 3-fluoro-2,5-di(4-octyloxyphenyl)pyridine. ##STR26## The compound has the phase sequence: X 88 (77.9) Sc 142 SA 171 N 172 I.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cccc(I)c1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cccc(I)c1)n1nnc2ccccc21

Procedure:
A suspension of 3-iodobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: O[CH2:2]/[C:3](/[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[C:4](/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)\[C:5]([NH:7][CH3:8])=[O:6].CCOCC.P(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][N:7]1[CH2:2][C:3]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:13][CH:14]=2)[C:5]1=[O:6]
Reactant: CNC(=O)/C(=C(\CO)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a 0° C. solution of (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide (430 mg, 1.01 mmol) in 1:1 ether:DCM (20 mL), PBr3 (0.114 mL, 1.21 mol) was added. The reaction mixture was stirred at RT for 2 h, diluted with DCM and basified with a NaHCO3 solution. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (350 mg, 85%) as a solid. 1H NMR (500 MHz, CD3OD): δ 8.81 (d, J=7.8 Hz, 2H), 8.24-8.19 (m, 2H), 8.11-7.94 (m, 3H), 7.85-7.80 (m, 1H), 7.59 (d, J=7.2 Hz, 2H), 7.44 (s, 2H), 7.21 (d, J=7.2 Hz, 2H), 5.61 (s, 2H), 3.38 (s, 2H), 3.09 (s, 3H). MS: M+H: m/z=408.2. HPLC: 89%, (Condition-B).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.CN(C=O)C.[C:23]1([C:29](=O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]/[C:29](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)O/C(=C/c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
Oxalyl dichloride (236 μl, 2.78 mmol) was added dropwise to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (500 mg, 2.78 mmol) in DCM (30 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the crude was taken up with pyridine (40 ml). 1,2-Diphenylethanone (546 mg, 2.78 mmol) was added, and the resulting suspension was heated under microwave irradiation at 140° C. for 1 hour. Pyridine was removed under vacuum, and the crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (E)-1,2-diphenylvinyl 1-methylpiperidine-4-carboxylate (62 mg).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.C1COCC1.[N:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:31]=S.Cl.C(N=C=NCCCN(C)C)C>O>[C:33]([NH:30][C:31]1[O:12][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=[C:2]3[I:1])=[N:13][N:14]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Reactant: CC(C)(C)N=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Temperature: 60 °C
Yield: 51.4 %

Procedure:
3-Iodo-1-tosyl-1H-indole-5-carbohydrazide (625 mg, 1.373 mmol) in a 250 mL RBF was treated with THF (25 mL) and 2-isothiocyanato-2-methylpropane (0.871 mL, 6.86 mmol) (Aldrich). The flask was fitted with a reflux condenser and heated at 60° C. for 2.5 h. The reaction was cooled to RT, the THF was removed in vacuo and replaced with DMF (10.00 mL). The solution was treated with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (395 mg, 2.059 mmol), fitted with a reflux condenser and heated to 80° C. for 2 h. The mixture was treated with H2O and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 0-100% EtOAc in Hex) to give N-tert-butyl-5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (378.7 mg, 0.706 mmol, 51.4) as a white amorphous solid. MS (ESI, pos. ion) m/z: 536.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98 (s, 1H), 7.90 (dd, J=8.7, 1.5 Hz, 1H), 7.69 (s, 2H), 7.43 (d, J=8.2 Hz, 2H), 2.33 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:29]([C:31]1[S:35][CH:34]=[C:33]([C:36]([OH:38])=[O:37])[CH:32]=1)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([CH2:29][C:31]3[S:35][CH:34]=[C:33]([C:36]([OH:38])=[O:37])[CH:32]=3)[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: O=Cc1cc(C(=O)O)cs1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)O)cs1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
To a solution of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile (0.1 g, 0.24 mmol) (Example 15a) in 1,2-DCE (4 mL) were sequentially added 5-Formyl-3-thiophenecarboxylic acid (0.045 g, 0.29 mmol) and sodium sulfate (150 mgs) under a nitrogen atmosphere at room temperature. The contents were stirred at room temperature for twenty hours and sodium triacetoxyborohydride (0.075 g, 0.336 mmol) was added. The reaction was allowed to continue at room temperature for six hours and quenched by the addition of water (15 mL). DCM (15 mL) was added, and sulfurdioxide gas was bubbled through the reaction mixture for ten minutes and the contents transferred into a separating funnel. The organic layer was separated, washed with brine (2×20 mL), dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography using DCM and MeOH to yield 0.1 g of the titled compound. Retention time: 3.09 min. YMC S5 Combiscreen 4.6×50 mm (4 minute gradient). Solvent A=10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B=90% MeOH, 10% water and 0.2% phosphoric acid.
Reaction SMILES: [CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[OH:38]>>[CH:1]([S:4]([O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[OH:38])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: NCCn1c(O)nc2cc(C3=NNC(=O)CC3)ccc21
Reactant: CC(C)S(=O)(=O)Oc1ccc(OCC2CO2)cc1
Product: CC(C)S(=O)(=O)Oc1ccc(OCC(O)CNCCn2c(O)nc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-(4-isopropylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[Na].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccc(-n2cncn2)n1
Temperature: 25 °C
Yield: 45 %

Procedure:
A stirred solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) and 1,2,4-triazole sodium salt (1.0 g, 9.9 mmol) in dimethylsulfoxide (10 ml) was heated at 60° C. for 5 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane, then dichloromethane containing 5% methanol, gave 2-bromo-6-(1H-[1,2,4]triazol-1-yl)pyridine (0.84 g) as a white solid: δH (400 MHz, CDCl3) 7.49 (1H, d, J 8), 7.74 (1H, dd, J 8 and 8), 7.87 (1H, d, J 8), 8.09 (1H, s), 9.15 (1H, s); m/z (ES+) 224/226 (M++H).