Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20](O)=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1.Cl.CN(C)CCCN=C=NCC.CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:30]1[C:29]([NH:28][C:20]([C:11]2([NH:10][C:8](=[O:9])[C:7]3[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:6]=3[O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:21])=[N:33][N:32]=[N:31]1
Reactant: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Reactant: Nc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C(=O)NC2(C(=O)Nc3nnn[nH]3)Cc3ccccc3C2)c1OC1CCC1
Yield: 68 %

Procedure:
A 40 mL tube is charged with 2-[(2-cyclobutoxy-3-methyl-benzoyl)-amino]-indan-2-carboxylic acid (323 mg, 0.884 mmol) and dry DCM (7 mL). A stirring bar is added and stirring is initiated. 5-Amino-1H-tetrazole (113 mg, 1.33 mmol) is added. To the resultant suspension, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (170 mg, 0.88 mmol) and 4-dimethylaminopyridine (108 mg, 0.88 mmol) is added. After 11½ days, tlc analysis (silica, 10% MeOH in DCM) indicates that the starting acid had been consumed. The reaction mixture is diluted with EtOAc (50 mL), transferred to an Erlenmeyer flask containing saturated aqueous ammonium chloride (50 mL). This mixture is allowed to stir. After 16 h of stirring, this mixture contained a white solid that is collected by suction filtration and washed with water (2×25 mL). Air drying gives 0.26 g of white powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[C:14]1([NH:20][OH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N+:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O-:21])=[CH:8][CH:7]=1
Reactant: ONc1ccccc1
Reactant: O=Cc1ccc(-c2ncco2)cc1
Solvent: CCO
Product: [O-][N+](=Cc1ccc(-c2ncco2)cc1)c1ccccc1
Temperature: 5 °C
Yield: 70.9 %

Procedure:
A mixture of 4-(2-oxazolyl)-benzaldehyde (1 eq., 6.3 gm) and N-phenyl-hydroxyamine (1 eq., 3.9 gm) was refluxed in ethanol (100 ml) for 30 minutes and concentrated to a volume of 50 ml. An equal amount (50 ml) of water was added and the mixture was cooled in a refrigerator at 5° C. overnight. White crystals were obtained, which were isolated by filtration and dried, producing 6.7 gm of 4-(2-oxazolyl)-phenyl-N-phenylnitrone.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)(C)(C)C.[ClH:31].CCOCC>CO>[ClH:31].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:13][CH:14]=1
Reactant: CN(C)c1nc(NCc2ccc(CNC(=O)OC(C)(C)C)cc2)nc2ccccc12
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN(C)c1nc(NCc2ccc(CN)cc2)nc2ccccc12
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a cooled solution of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (3.90 g, 9.57 mmol) in MeOH was added 1 M HCl in Et2O (67.0 ml, 67.0 mmol) and the solution was stirred for overnight. The resulting mixture was concentrated to give N2-(4-aminomethyl-benzyl)-N4,N4-dimethyl-quinazoline-2,4-diamine hydrochloride as a white crystalline solid (3.48 g, 95.6%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:15]1(=[O:20])[N:14]([O:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:3])[C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(B(O)O)cc1
Reaction time: 0.17 h

Procedure:
4-Carboxyphenyl-boronic acid (CPBA, Example 1, 0.25 g, 1.51 mmol) and N-hydroxysuccinimide (0.26 g, 2.26 mmol) were dissolved in 8.5 ml DMF using a magnetic stirrer. 20 ml of dichloromethane (CH2Cl2) was then added, and the solution was stirred for 10 minutes. N,N'-dicyclohexyl-carbodiimide (DCC, 0.93 g, 4.52 mmol) in 3 ml CH2Cl was then added. The solution was left to react under a nitrogen atmosphere overnight (approx. 12 hours) at ambient temperature, and then filtered to remove the insoluble urea byproduct (DCU). The title compound was used in subsequent reactions without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].Br[CH:16]([C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOCC>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([O:1][CH:16]([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a nitrogen flushed 5 L three neck round bottom flask fitted with a mechanical stirrer, condenser, and a nitrogen inlet was charged 326 g (1.68 mol) of methyl 4-hydoxy-3-n-propylbenzoate, 507.6 g (1.73 mol)of ethyl α-bromo-3,4-methylenedioxyphenylacetate from above, 235 g (1.70 mol) of anhydrous potassium carbonate, and 1.7 L of acetone. The mixture was refluxed with vigorous stirring for 9 hr. The suspension was allowed to cool to ambient temperature and stirred overnight. The mixture diluted with 2 L of ether, cooled to 0° C. and filtered through Super-CelR. The cake washed with ether and the combined filtrate concentrated. The residue was redissolved in ether and the organic layer washed with once with 1 N HCl, saturated sodiuim bicarbonate solution, 10% sodium bisulfite solution, brine, dried with magnesium sulfate, treated with charcoal and filtered through a plug of silica. The pale yellow solution was concentrated to 697.3 g (theoretical 678 g) of a thick yellow oil which was used without purification in the next step. NMR was consistent with the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CCC>[CH3:13][O:12][C:9]1[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:20][CH2:21]3)[C:11]=2[N:10]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
4-Chloro-6-methoxy-8-methylpteridin-7(8H)-one (4.00 g, 17.7 mmol, 1 equiv) and 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (3.83 g, 17.7 mmol, 1 equiv) were suspended in anhydrous n-butanol (40 mL) in a 250 mL one-necked round-bottomed flask. Triethylamine (35.30 mmol, 3.57 g, 4.92 mL, 2 equiv) was added to the flask, and the stirred reaction mixture was heated to 80° C. The reaction was monitored by LC/MS and was complete after 6 hours. The resulting tan colored suspension was cooled to room temperature and filtered. The collected solid was washed with n-butanol (10 mL) and anhydrous ether (25 mL). The solid was air-dried to give the desired material, 6-methoxy-8-methyl-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one as a pale yellow colored solid (5.69 g, 79% yield.). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (broad s, 1H), 8.33 (s, 1H), 7.13 (m, 1H), 6.93 (m, 3H), 5.30 (d, 1H), 4.54 (1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.20 (t, 2H), 2.42 (dq, 2H), 1.82 (d, 2H). MS (EI) for C20H21N7O3: 408 (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([P:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[O:5]=[C:4]1[CH2:3][CH:2]([CH2:1][P:13](=[O:14])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6]1
Reactant: OP(c1ccccc1)c1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1CC(CP(=O)(c2ccccc2)c2ccccc2)O1

Procedure:
A mixture of 4.2 parts of diketene, 10.1 parts of diphenylphosphinous acid, 2.3 parts of bis-(t-butylcyclohexyl)-perdicarbonate and 70 parts of toluene was stirred by a stream of nitrogen in a quartz apparatus at room temperature while being irradiated by UV light from a medium pressure mercury lamp. After three hours irradiation, the reaction mixture was filtered, and the filtrate evaporated. The semi-crystalline residue was triturated with a little toluene, and the crystals collected on a filter and washed with toluene. Crystallisation from toluene gave colourless crystals of (2-oxo-4-oxetanylmethyl)-diphenylphosphine oxide which melted at 154°-155° C. and had the following elemental analysis by weight.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([OH:11])=[O:10])[N:3]=1.[NH2:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=1.C(=O)([O-])[O-].[Na+:23].[Na+]>O>[Na+:23].[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[CH:5]=[C:4]([C:9]([O-:11])=[O:10])[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(O)c1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Nc2cc(C(=O)[O-])nc(Cl)n2)n[nH]1
Yield: 57.1 %

Procedure:
A mixture of 2,4-dichloropyrimidin-6-yl carboxylic acid (Method 45) (528 mg, 2.73 mmol), 3-amino-5-methylpyrazole (279 mg, 2.87 mmol) and sodium carbonate (578 mg, 5.46 mmol) was heated in water (10 ml) at 50° C. for 18 hours. The mixture was allowed to cool and the product was collected by filtration, washed with water and dried to give the title compound (430 mg, 77%).
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:22])[C:19]([Cl:21])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[I-].[K+].[CH3:26][O:27][CH2:28]Cl>C(O)C>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([O:22][CH2:26][O:27][CH3:28])[C:19]([Cl:21])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc3ccoc23)C1
Reactant: COCCl
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COCOc1cc2c(cc1Cl)CCN(C)CC2c1cccc2ccoc12
Reaction time: 3 h

Procedure:
(+)-5-(7-benzofuranyl)-8-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (1.64 g, 0.005 mol) is suspended in dry ethanol (50 ml). Potassium-tert.-butylate (1.12 g, 0.010 mol) and potassiumiodide (0.10 g) are added. To the resulting solution chloromethyl methyl ether (0.84 g, 0.010 mol) is added. The reaction mixture is stirred for 3 hours. The resulting suspension is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is chromatographed on a silicia-gel column, using dichloromethane/methanol (25:1) as the eluent. The fractions containing the product are collected and evaporated to dryness under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[O:6][CH:23]=[N:22][CH:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccccc1-c1cnco1
Yield: 70.4 %

Procedure:
A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol), tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate (10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours. The solvent is removed under reduced pressure and the residue poured into ice-water (800 ml). The precipitate is collected by filtration, washed with water, and dried in vacuo to give 9.05 g of 5-(2-methoxyphenyl)oxazole (70%). Boron tribromide (1M in dichloromethane, 36 ml) is added slowly to a cold solution (0° C.) of the above oxazole (3.0 g, 17.1 mmol) in dichloromethane (215 ml). After stirring overnight at room temperature, ice-water (50 ml) is added carefully. The aqueous layer is extracted with dichloromethane (50 ml), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The precipitate which formed after addition of dichloromethane (70 ml) is collected by filtration, heated with dichloromethane (15 ml), and filtered again to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 400 mg of the title epoxide (9.5%).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(Cl)(=O)C([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([Cl:19])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A stirred solution of 10.0 g (0.04 mole) of (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid in 100 ml of toluene was heated to 80° C. To this solution at 80° C. was added dropwise over 10 minutes a solution of 10.5 g (0.08 mole) of oxalyl chloride in 5 ml of toluene, and the whole heated at 80° C. for 26 hours. The toluene and excess oxalyl chloride were removed by distillation to give a residual oil which was distilled under reduced pressure using a Kugelrohr distilling system to give 8.2 g of (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride; b.p. 85° C./0.09 mm. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>CN(C=O)C.[Pd]>[CH3:14][O:13][C:11]1[CH:12]=[C:4]([NH2:1])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)O)c(N)c1
Yield: 83.5 %

Procedure:
2-Nitro-4-methoxybenzoic acid (43.4 g, 0.22 mol) in DMF (250 ml) was hydrogenated at 55 psi in the presence of 10% palladium on carbon (5.8 g) for 2.5 hours. The reaction mixture was filtered through SUPERCELL®, the filter cake was rinsed with ethanol and then the filtrate was poured into ice/water (3.5 L). A precipitate formed which was collected by filtration, washed with water and dried in an oven at 60° C. to afford 30.7 g (84%) of 4-methoxyanthranilic acid, m.p. 176-178° C. (dec.).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CN(C)CCN
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN(C)C)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride obtained in Step III as describe above (586 mg; 1.41 mmol; 1 eq), is dissolved in anhydrous DCM (15 ml). The reaction is put under nitrogen. Triethylamine (1.9 ml; 14.1 mmol; 10 eq) and N,N-dimethyl-ethane-1,2-diamine (0.17 ml; 2.82 mmol; 2 eq) are added successively and the reaction mixture is stirred at room temperature for 30 minutes. The solvents are evaporated and the crude mixture is purified by preparative HPLC, affording the title compound (68 mg; 10%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[C:2]1[CH:8]=O.COP([CH:16]([NH:20]C(=O)C)[C:17](=[O:19])[CH3:18])(=O)OC.C1CCN2C(=NCCC2)CC1>ClCCl>[S:1]1[C:2]2=[CH:8][N:20]=[C:16]([C:17](=[O:19])[CH3:18])[CH:6]=[C:3]2[CH:4]=[CH:5]1
Reactant: O=Cc1ccsc1C=O
Reactant: COP(=O)(OC)C(NC(C)=O)C(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)c1cc2ccsc2cn1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 2,3-thiophenedicarboxaldehyde (600 mg, 4.28 mmol) in dichloromethane (50 ml) was cooled to 0° C. under an atmosphere of nitrogen. (1-Acetylamino-2-oxo-propyl)-phosphonic acid dimethyl ester (1.05 g, 4.70 mmol) was added [literature procedure: Kitamura, et al. Tet. Lett., 36(32), 1995, pp. 5769-5772], followed by DBU (0.471 ml, 4.70 mmol), and the mixture allowed to warm to ambient temperature overnight, then concentrated in vacuo, and the residue was then purified by flash chromatography (0-50% ethyl acetate in hexanes) to provide 1-thieno[2,3-c]pyridin-5-yl-ethanone as a white solid (326 mg, 43%). 1HNMR (250 MHz, CDCl3): δ 9.20 (s, 1H), 8.50 (d, 1H, J=1.02), 7.80 (d, 1H, J=5.36), 7.51 (d, 1H, J=5.36), 2.81 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](O)=[O:21])=[O:17])=[CH:10]2>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:20]([CH:19]([NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:2]
Reactant: CCNCC
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Diethylamine (1.2 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.6 mmol) were coupled according to procedure A (0-25° C. for 5 days) substituting the following workup: the crude product was suspended in 1:1 chloroform/dichloromethane, sonicated, filtered to remove solids, concentrated, and the residue purified by column chromatography on silica gel eluted with 10, 20 and 30% ethyl acetate in hexanes: Yield 14 mg, 6%; HPLC (60/40) 8.88 minutes (98%); PBMS 398/400 (MH+, 100%);
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-])=O)[CH:8]=2)=[N:3]1>CO.CCOC(C)=O.[Ni]>[CH3:1][N:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:11])=[CH:12][CH:13]=2)[NH:3]1
Reactant: Cn1nnc(-c2ccc(N)c([N+](=O)[O-])c2)n1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1NN=C(c2ccc(N)c(N)c2)N1
Yield: 98.4 %

Procedure:
4-(2-Methyl-2H-tetrazol-5-yl)-2-nitroaniline (8-3) (242 mg, 1.1 mmol) in MeOH-EtOAc (1:1, 200 mL) was hydrogenized (H2 pressure 50 psi) in the presence of Raney-Ni (35 mg) overnight. After this time, the reaction solution color was changed from yellow to colorless. LCMS indicated that the starting material was completely disappeared but the product peak was weak. The catalyst was filtered and washed with MeOH (2×20 mL). The collected MeOH-EtOAc solution was concentrated to afford the desired pure product (8-4) (208 mg, 100%) according to 1H NMR. 1H NMR (500 MHz, DMSO-d6): δ7.26 (d, J=2.0 Hz, 1H), 7.12 (dd, J=8.0, 2.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), (s, 2H), 4.93 (s, 2H), 4.72 s, 2H), 4.34 (s, 3H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[C:4]2([C:14]3[CH:13]=[CH:12][S:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[NH:3][C:2]1=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>O1CCOCC1>[S:25]=[C:2]1[NH:3][C:4]2([C:14]3[CH:13]=[CH:12][S:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[C:5](=[O:6])[NH:1]1
Reactant: O=C1NC(=O)C2(CCCc3sccc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CCCc1sccc12
Temperature: 120 °C
Yield: 100.7 %

Procedure:
6,7-Dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazolidine]-2′,5′-dione (0.5 g, 2.25 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (0.91 g, 2.25 mmol) were suspended in 1,4-dioxane (5 mL). The mixture was heated by microwave irradiation at 120° C. for 30 min. The solution was concentrated in vacuo and the crude residue purified on silica gel using a gradient elution of 20-100% ethyl acetate in 40-60 petroleum ether. Isolated material was further purified on silica gel using a gradient elution of 2-5% methanol in dichloromethane to afford the title compound as a colourless solid (0.54 g, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(1-methyl-piperidin-4-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-phenyl)-1-methyl-piperidine; hydrochloride (100.0 mg, 0.3441 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.070 g, 58%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.8 Hz, 1H), 8.23 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.1 Hz, 2H), 7.65 (d, J=7.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.01 (t, J=6.7 Hz, 1H), 6.85 (s, 1H), 3.10 (s, 3H), 3.01-2.94 (m, 2H), 2.51-2.41 (m, 1H), 2.33 (s, 3H), 2.10-2.01 (m, 2H), 1.87-1.77 (m, 4H). MS=462 (MH)+.
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(OC(=O)C)(=O)C.[OH:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](=[O:22])[NH:18][N:17]=1)=[NH:15]>N1C=CC=CC=1>[CH3:1][C:2]1[O:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][N:17]=2)[N:15]=1
Reactant: CC(=O)O
Reactant: N=C(NO)c1ccc(=O)[nH]n1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(=O)[nH]n2)no1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
2.8 ml of glacial acetic acid, 2.3 ml of acetic anhydride and 200 μl of pyridine are added to 375 mg (2.43 mmol) of N-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxamidine, and the mixture is stirred at 90° C. for 15 h. During cooling of the reaction mixture, a precipitate forms, which is filtered off with suction, washed with water and dried in vacuo; yield: 253 mg, yellow solid; HPLC: Rt=1.51 min; LC-MS: 179 (M+H).