Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Product: c1ncn(-c2nc(NCc3ccc4c(c3)OCCO4)c3c4c(sc3n2)CCCC4)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:27](=[O:29])[CH3:28])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reaction time: 3 h
Yield: 64 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol) in 10 mL DCM at 0° C. was added acetyl chloride (0.02 g, 0.27 mmol) followed by pyridine (0.02 g, 0.21 mmol). After stirring for 3 h, reaction was concentrated and purified by flash chromatography on silica gel with 50% EtOAc/hexane to obtain the product in 64% yield.
Reaction SMILES: C(OC([C:6]1[C:15](=[O:16])[N:14]2[CH:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)[CH:8]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:7]=1)=O)C.C([O-])(O)=O.[Na+]>Cl>[N:17]1([CH:8]2[CH:9]3[N:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)[C:15](=[O:16])[CH:6]=[CH:7]2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C1=CC(N2CCN(C(=O)OC(C)(C)C)CC2)C2C=CC=CN2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1C=CC(N2CCNCC2)C2C=CC=CN12
Yield: 40.7 %

Procedure:
A mixture of 1-(4-tert-Butoxycarbonyl-piperazin-1-yl)-4-oxo-1,9a-dihydro-4H-quinolizine-3-carboxylic acid ethyl ester (0.320 g, 0.797 mmol) in concentrated HCl (5 mL) was refluxed for 30 minutes. After cooling, the reaction was basified with aqueous NaHCO3 solution and thoroughly extracted with DCM. The combined organic layers were washed with brine, dried and concentrated to give 1-Piperazin-1-yl-1,9a-dihydro-quinolizin-4-one (0.075 g, 41%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 9.16 (d, J=7.2 Hz, 1H), 8.20 (d, J=9.2 Hz, 1H), 7.71 (d, J=9.6 Hz, 1H), 7.37 (t, J=7.2 Hz, 1H), 7.03 (t, J=6.4 Hz, 1H), 6.61 (d, J=9.2 Hz, 1H), 3.07 (m, 4H), 2.87 (m, 4H). LCMS (APCI+) m/z 230 [M+H]+; Rt=0.29 min.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.CCOCC>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCCCCOC1CCCCO1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(CCCCCCOC1CCCCO1)C(=O)OCC
Temperature: 60 °C

Procedure:
Sodium (1.13 g, 49 mmol) in small quantities was dissolved in dry ethanol (100 ml) with constant stirring under a blanket of dry nitrogen. Diethyl malonate (8.0 g, 50 mmol) was added in one portion and the solution heated at 60° C. for 1 hour. 2-(6-Chloro-hexyloxy)-tetrahydropyran (9.3 g, 42.2 mmol) was added in one portion and the temperature raised to 75-80° C. and maintained at this level for 24 hours. After cooling, the inorganic solid was removed by filtration and solvent evaporated from the filtrate. The residue was dissolved in CH2Cl2 (50 ml), extracted with water (30 ml×2), dried (MgSO4) filtered and volatiles removed to leave a pale yellow oil. This oil was subject to chromatography on silica gel using pet ether 40:60/ether (200:40) as the eluent. The required product eluted with an rf=0.15 and was isolated as a colourless oil. Yield 8.7 g, (60%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)#[C:2][CH3:3].C(N(CC)CC)C>CCO.[Pd]>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CC#Cc1ccc(C(=O)O)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)O)cn1
Yield: 97.6 %

Procedure:
A solution of the product of Step A (0.25 g; 1.55 mmol), 10% Pd/C (0.15 g) and triethylamine (0.5 ml) in EtOH (15 ml) was stirred overnight at room temperature under H2 (Parr apparatus; 100 psi). The catalyst was removed by filtration, washed with fresh EtOH (2×10 ml), and combined filtrates were evaporated to dryness to give the title compound (0.25 g; 100%), as greyish solid, which was used in the next Step without further purification. 1H-NMR (CDCl3) 0.94 (tr, 3H, J=6 Hz); 1.69-1.81 (m, 2H); 2.83 (tr, 2H, J=6 Hz); 7.2 (d, 1H, J=9 Hz); 8.19 (s, 1H); 8.28 (d, 1H, J=9 Hz); 10.65 (broad s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])[CH2:6][CH2:7]1
Reactant: CC(C)C(=O)NC1CCC(O)CC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)C(=O)NC1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22b from N-(4-hydroxycyclohexyl)isobutyramide (Example 40c) and 2-amino-6-fluorobenzonitrile as an off-white solid (99%). MS 302 (MH+).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH3:12][CH2:13]O>>[OH:2][CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1
Reactant: O=C(O)C1CNCC(O)C1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1CNCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Anhydrous HCl was bubbled through a suspension of (±)-5-hydroxypiperidine-3-carboxylic acid (5.6 g, 38.6 mmol) (according to the procedures as disclosed in J. Med. Chem., 25, 1157-1162, (1982)), cooled to 0° C. in EtOH (100 mL), until saturation was reached. The reaction mixture was warmed to room temperature, stirred overnight, then concentrated in vacuo. The crude salt was cooled to 0° C. in CHCl3 (80 mL), and anhydrous NH3 was bubbled through the solution. The resulting white precipitate was removed by vacuum filtration, and the filtrate was concentrated in vacuo to provide 6.6 g (99%) of (±) ethyl 5-hydroxypiperidine-3-carboxylate as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:27][C:28]=3[CH3:29])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (519 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionic acid (459 mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 142–143° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCOc1nc(C)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 103 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with ethanesulfonylchloride to give 92 mg 4-tert.-butyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=5.12 min, [M+1]+=579.60, [M−1]−=577.72.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:32])=[O:31]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)ccc1Oc1cncc(Cl)c1
Yield: 92 %

Procedure:
The title compound was prepared using the alternative procedure described in Example 3. In this manner, 0.1 g of the aniline of Example 1 was combined with 2,4-dichloro-6-methylbenzenesulfonyl chloride and polyvinyl pyridine to provide 0.162 g (92%) of the title sulfonamide after chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[N:32]=[C:31]([C:33](Cl)=[O:34])[CH:30]=[CH:29][N:28]=1)(=O)=O.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:13][N:12]2[C:33]([C:31]2[CH:30]=[CH:29][N:28]=[C:27]([S:24][CH3:23])[N:32]=2)=[O:34])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC1CNN(C(=O)Cc2ccc(F)cc2)C1
Reactant: CS(=O)(=O)c1nccc(C(=O)Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSc1nccc(C(=O)N2CC(OC(=O)C(C)(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of 2,2-dimethyl-propionic acid 1-[2-(4-fluorophenyl)acetyl]-pyrazolidin-4-yl ester, 32, (427 mg, 1.79 mmol) in dichloromethane (3 mL) is added 2-methylsulfonyl-pyrimidine-4-carbonyl chloride (676 mg, 3.58 mmol) followed by dropwise addition of a 1.0 N aqueous solution of sodium hydroxide (6 mL). The mixture is vigorously stirred at room temperature for 12 hours. The reaction is diluted with dichloromethane (25 mL) and washed with water (25 mL). The aqueous layer is back-extracted with dichloromethane (25 mL). The combined organic layers are washed with a saturated aqueous solution of sodium bicarbonate (25 mL) and brine (25 mL), dried, filtered and concentrated in vacuo. The resulting crude material is purified over silica (1:1 hexane/ethyl acetate to 100% ethyl acetate) to afford 464 mg (96.6% yield) of the desired product as a brown, viscous oil.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CCN(CC)CC.C1C=CC=CC=1.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>[CH3:17][Si:18]([C:21]#[C:22][C:2]1[CH:16]=[CH:15][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCN(CCCC)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCN(CCCC)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Cuprous iodide (23 mg, 1 mol %) was added to 4-iodo-N,N-dibutylaniline (4 g, 12.1 mmol), trimethylsilylacetylene (2.37 g, 24.2 mmol) and Pd(PPh3)2Cl2 (84 mg, 1 mol %) in dry Et3N (40 mL) under nitrogen. The resulting solution was stirred at room temperature for 16 h, diluted with benzene (50 mL), filtered and the solvent removed under reduced pressure. The residue was chromatographed on alumina using benzene as eluent. The solvent was removed under reduced pressure to give the title compound (3.0 g, 82%) as a pale yellow oil.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Cl.[CH3:21][NH2:22].[OH-].[Na+]>O>[CH3:21][NH:22][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1
Reactant: CN
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(NC)ccc3C[C@@H]21
Temperature: 240 °C
Yield: 57.2 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (1.00 g, 3.32 mmol) and methylamine hydrochloride (10 g) was heated to 240° C. to form a homogeneous molten semi-solid. After 30 minutes the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown solid. Purification by flash chromatography (10% methanol in methylene chloride, NH4OH) provided (±)-trans-2-methylamino-6-propyl-5,5a,6,7,8,9, 9a,10-octahydropyrido[2,3-g]quinoline (Rf=0.44, 493 mg 57% yield) as an orange solid. This material was converted to the dihydrochloride salt in a manner analogous to that set forth in Example 3. Recrystallization (methanol/ethyl acetate) gave the desired dihydrochloride as a tan solid. m.p.>250° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>N1C=CC=CC=1.C(Cl)Cl>[CH3:12][C:8]1[CH2:7][CH2:6][CH:5]2[C:9]=1[CH2:10][CH2:11][CH:2]([O:1][C:14](=[O:17])[CH2:15][CH3:16])[CH2:3][C:4]2=[CH2:13]
Reactant: CCC(=O)Cl
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C1CC(OC(=O)CC)CCC2=C(C)CCC12
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 2.5 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene in 5 ml of pyridine and 50 ml of methylene chloride was treated at -10° with 1.73 ml of propionyl chloride. After 3 hours stirring, the solution was poured on to ice and worked up in a conventional manner. After distillation of the crude product under high vacuum, there were obtained 3.15 g (96%) of pure 1-methyl-4-methylene-6-propionyloxy-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.05 65°-70°; IR(film): νmax = 1380, 1730, 1640, 1460, 1440, 1375, 1340, 1270, 1190, 1158, 1080, 1018, 895 cm-1. The compound has a woody, spicy, balsamic, slightly earthy odour.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].C(N(CC)CC)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>COCCOC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:25](=[O:26])[NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccccc1
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 3.1 g of 2-pyrroloylacetonitrile in 25 ml of glyme (ethylene glycol dimethyl ether) and 2.7 g of anhydrous triethylamine is treated with 3.0 g of phenyl isocyanate. After the moderately exothermic reaction, the mixture is let stand overnight. Most of the solvent is evaporated and the residue is treated with water and 12 ml of 10% NaOH solution. The aqueous, alkaline solution is washed with ethyl acetate and acidified with 6N HCl. The product is collected, washed with water, dried and recrystallized from ethanol, to give β-oxo-α-(phenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 207°-209°, the compound of formula II, wherein R1 to R4 are hydrogen.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3ccccn3)ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccc(-c3ccccn3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[C:20]([C:21]([OH:23])=O)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:20]3[C:11](=[O:10])[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccccc2[nH]c1=O
Temperature: 25 °C

Procedure:
DIEA (50.7 μL, 0.29 mmol) was added to 2-Oxo-1,2-dihydro-quinoline-3-carboxylic acid (50.0 mg, 0.26 mmol) and HATU (110.6 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (55.3 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 381 (MH+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([N:24]=[CH:25][N:26]=3)[C:10](=[O:23])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.O1CCCC1.Cl.C(=O)(O)[O-].[Na+]>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:12]3[N:13]=[C:4]([CH:3]=[O:2])[CH:5]=[CH:6][C:7]=3[C:8]3=[N:26][CH:25]=[N:24][N:9]3[C:10]2=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3ccc(C(OC)OC)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3ccc(C=O)nc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
8-(Dimethoxymethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (682 mg, 1.79 mmol), tetrahydrofuran (20 ml), water (5 ml) and 12 N hydrochloric acid (3 ml) were combined and stirred at room temperature for 20 hours. The mixture was neutralized slowly with powdered sodium bicarbonate to pH 8. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried (MgSO4) and concentrated to afford 516 mg (77%) of the aldehyde as a yellow foam, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.73-3.81 (m, 3H), 5.83, (s, 2H), 6.85 (d, J=8.66 Hz, 2H), 7.64 (d, J=8.53 Hz, 2H), 8.03 (d, J=7.78 Hz, 1H), 8.42 (s, 1H), 8.83 (d, J=7.91 Hz, 1H), 10.22 (s, 1H). LCMS (MH+, 336.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11]>CO.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
Under H2, a mixture of 2-fluoro-4-nitrophenol (10 g, 63.7 mmol) and Pd/C (1 g) in methanol (100 mL) was stirred at room temperature for 5 hours. The mixture was filtered, and concentrated in vacuo to give the compound 2A-1 (7 g, yield 86%).
Reaction SMILES: [CH2:1]([CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1)[NH2:17]>>[CH2:1]([C:8]1[C:12]([CH3:13])=[N:17][N:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:26])=[CH:22][CH:23]=2)[C:9]=1[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(CCO)cc1
Reactant: CC(=O)C(Cc1ccccc1)C(C)=O
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-benzylpentane-2,4-dione and 2-(4-hydrazinophenyl)ethanol hydrochloride: 1H-NMR (CDCl3) δ 7.39-7.15 (9H, m), 3.89-3.85 (2H, t, J=6.4 Hz), 3.48 (2H, s), 2.91 (2H, t, J=6.6 Hz), 2.29 (3H, s), 2.21 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=1>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1F
Reactant: Cc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 4-amino-3-fluorophenol (5.00 g, 39.3 mmol) in anhydrous DMA (100 mL) was treated with potassium tert-butoxide (5.30 g, 47.2 mmol), and the red-brown mixture was stirred at room temperature for 1 h. The mixture was treated with a solution of 4-chloro-2-picoline (5.02 g, 39.3 mmol) in anhydrous DMA (75 mL) and then heated at 100° C. for 17 h. The mixture was cooled to ambient temperature and partitioned between EtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated at reduced pressure. Purification through a silica gel plug, eluting with 40% EtOAc/hexane, followed by crystallization from DCM/hexane afforded 4.06 g (47%) of the title compound as a yellow solid. 1H-NMR (DMSO-d6) δ 8.24 (d, J=5.4 Hz, 1H), 6.91 (dd, J=12.3, 2.7 Hz, 1H), 6.80 (dd, J=9.6, 8.7 Hz, 1H), 6.72 to 6.62 (m, 3H), 5.15 (broad s, 2H), (2.36 (s, 3H); MS LC-MS [M+H]+=219, RT=0.24 min.