Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5](=[O:20])[C:6]([C:18]#[N:19])=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[O:16][CH3:17])[CH3:8]>C(OCC)C.[Cu]I>[CH3:3][O:4][C:5](=[O:20])[CH:6]([C:18]#[N:19])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:1])[CH3:8]
Reactant: COC(=O)C(C#N)=C(C)c1ccc(F)cc1OC
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C(C#N)C(C)(C)c1ccc(F)cc1OC
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a chilled (0° C.) suspension of 4.3 g (22.58 mmol) of copper (I) iodide (purified by Soxhlet extraction with THF) in 100 mL of diethyl ether was added 26 mL (41.60 mmol) of a 1.6 M solution of methyl lithium in ether over a 15 minute period. After the addition, the mixture stirred for 10 min and was then cooled to −25° C. and a solution of 4.0 g (15.19 mmol) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)but-2-enoic acid methyl ester in 50 mL of diethyl ether was added over a 20 minute period. The mixture stirred at −25° C. for 30 minutes and was then allowed to warm to room temperature. The reaction was monitored by proton NMR. After 1.5 hours, an aliquot partitioned between EtOAc and 1 N aqueous HCl indicated starting material was gone and desired product was present. The reaction was cautiously poured into brine and then saturated aqueous ammonium chloride was added followed by 1 N aqueous HCl and EtOAc. The mixture was filtered through diatomaceous earth and the aqueous layer was separated and extracted with three 50 mL portions of EtOAc. The combined organic layers were washed with 30 mL of 1 N aqueous HCl, 30 mL of brine, and three 25 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford 4.2 g (99%) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester.
Reaction SMILES: [N:1]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][N:2]=1.N1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]CCCN1>>[NH2:2][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([NH2:1])[CH:20]([CH2:19][CH3:18])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]([CH2:4][CH3:3])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C1CCCCCNNCCCC1
Reactant: C1=CCCN=NCCC=CCC1
Product: CCCCC(CC)C(N)CCCCCCCCC(N)C(CC)CCCC

Procedure:
The 1,2-diaza-1,5,9-cyclododecatriene and 1,2-diazacyclododecane, used as starting products, can be produced by the methods described in the German Offenlegungsschriften Nos. 2,330,087 and 2,549,403.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.[Cl:18][C:19]1[C:20]([C:41]#[N:42])=[C:21]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])=[N:34][CH:35]=2)[C:22]([O:28][CH3:29])=[C:23]([CH:25](Cl)[CH3:26])[CH:24]=1>CN(C)C=O.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:25]([C:23]3[C:22]([O:28][CH3:29])=[C:21]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:39])[CH3:40])=[O:37])=[N:34][CH:35]=4)[C:20]([C:41]#[N:42])=[C:19]([Cl:18])[CH:24]=3)[CH3:26])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Cesium carbonate (3000 mg, 10 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1100 mg, 7.1 mmol) and 5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide (1.8 g, 4.8 mmol) in N,N-dimethylformamide (50 mL). The reaction was stirred at 80° C. for 3 hrs and was allowed to cool to room temperature. The reaction was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated to give the crude product. This was purified by FCC on silica gel eluting (hexanes/10% EtOH in EtOAc, 0-100%) gradient to give the title compound as light yellow oil (2.0 g, 80%). LCMS calculated for C24H24ClN8O2 (M+H)+: m/z=491.1; found: 491.2. NMR (400 MHz, CD3OD) δ 8.74 (d, J=1.4 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.13 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 6.43 (q, J=7.0 Hz, 1H), 3.32 (s, 3H), 3.16 (s, 3H), 3.07 (s, 3H), 2.64 (s, 3H), 1.89 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(O)[C@H]1[O:35][C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO>>[OH:35][C:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])([CH3:1])[CH3:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h

Procedure:
Fifty ml of the conversion culture medium described in Examples 1-9 was placed in a 250 ml Erlenmeyer flask and autoclaved at 120° C. for 20 minutes. This medium was inoculated with 1 ml of the seed culture solution prepared as in Examples 1-9 and shaking culture was carried out at 220 rpm for 48 hours at 28° C. To this culture were added cholesterol in the form of powder and 5.6 ml of a 1.5% aqueous solution of partially methylated β-cyclodextrin (methylation rate 74%: Mercian Corp.) which was sterilized beforehand, and the cultivation continued for further 40 hours. By the same method as Examples 1-9, 25-hydroxycholesterol in the culture solution obtained was quantified. The conversion rates into 25-hydroxycholesterol from cholesterol were summarized in Table 3.
Reaction SMILES: [CH3:1]COCC.C[Si](C=[N+]=[N-])(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([C:42]([OH:44])=[O:43])[C:17]2[C:18]([CH:41]=1)=[N:19][N:20]([CH2:22][C:23]([C:39]#[N:40])([NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[O:27])[CH3:24])[N:21]=2>C1COCC1.CO>[Cl:13][C:14]1[CH:15]=[C:16]([C:42]([O:44][CH3:1])=[O:43])[C:17]2[C:18]([CH:41]=1)=[N:19][N:20]([CH2:22][C:23]([C:39]#[N:40])([NH:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=1)=[O:27])[CH3:24])[N:21]=2
Reactant: CCOCC
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(C(=O)O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(OC(F)(F)F)cc3)nc12
Reaction time: 8 h
Yield: 40 %

Procedure:
A 2 molar ether solution of trimethylsilyldiazomethane was added to 6-chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}amino)-propyl]-2H-benzotriazole-4-carboxylic acid (100 mg) dissolved in a ten to 1 one mixture of THF and methanol (2 mL). After overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (42 mg, 40%). MS (ES): M/Z [M+H]=482. 1H NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 3.78 (s, 3H), 5.44 (d, J=13.3 Hz, 1H), 5.58 (d, J=13.3 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H), 8.02 (d, J=1.9 Hz, 1H), 8.52 (d, J=1.9 Hz, 1H) and 8.87 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([F:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]1[C:21]#[N:22])=[O:14]>>[F:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]3[C:21]#[N:22])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: NC12CCC(F)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(F)(CC1)CC2
Yield: 89.7 %

Procedure:
Using 4-amino-1-fluorobicyclo[2,2,2]octane (50.0 mg) and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (82.1 mg), the same procedure was followed as in Example 10 to obtain (2S,4S)-1-[[N-(4-fluorobicyclo[2,2,2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (93.1 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][CH2:12][CH2:13]O>OS(O)(=O)=O.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][CH2:12][Cl:11])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(OCCCl)c1cccc(O)c1

Procedure:
A solution of 65 g of 3-hydroxybenzoic acid (0.47 mol) in 500 mL of 2-chloroethanol and 3 mL of H2SO4 was refluxed for 4 hours. The cooled solution was diluted with 500 mL of water and extracted with ethyl acetate (3×250 mL). The ethyl acetate was extracted twice with aqueous NaHCO3 and then with water. The ethyl acetate solution was dried and evaporated under reduced pressure yielding 85 g of product as a thick oil; 1H NMR (CDCl3) δ3.814 (t,2H, J=6 Hz), 4.569 (t,2H, J=6 Hz), 5.36 (br s,1H), 7.06-7.67 (m,4H). ##STR12##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>CC(O)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][N:21]=[C:20]2[N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CCCCCCC(C)Nc1ccc2c(c1)CCN2
Solvent: CC(C)O
Product: CCCCCCC(C)Nc1ccc2c(c1)CCN2c1ncnc2cc(OC)c(OC)cc12
Yield: 96 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 96% yield from [2,3-dihydro-1H-indol-5-yl]-(1-methyl-heptyl)-amine (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 61°-63° C.; GC-MS: 434 (M+); anal. RP18-HPLC RT: 6.91 min.).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:14](Br)([F:16])[F:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N>CN(C)C(=O)C.C(Cl)Cl.[Zn]>[F:15][C:14]([F:16])=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: FC(F)(Br)Br
Agent: N#N
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCC(=C(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (0.47 mL, 2.94 mmol) and dibromodifluoromethane (0.54 mL, 5.88 mmol) in N,N-dimethylacetamide (3.5 mL) was added triphenylphosphine (1.54 g, 5.88 mmol) in N,N-dimethylacetamide (3.5 mL) dropwise under N2 at 0° C. over 15 min. The reaction mixture was stirred at ambient temperature for 1 h, then zinc (0.384 g, 5.88 mmol) was added over 1 min. The mixture was stirred at rt for 20 min and then heated at 70° C. for 16 hr. The reaction was diluted with DCM, filtered through diatomaceous earth (Celite®) and the filtrate was washed with sat. NaHCO3, water and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to an oil. The crude product was charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0-20% EtOAc in hexane to yield ethyl 4-(difluoromethylene)cyclohexanecarboxylate (0.015 g). 1H NMR (400 MHz, CDCl3) ppm 4.10-4.20 (2H, m), 2.35-2.52 (3H, m), 1.95-2.05 (2H, m), 1.79-1.93 (2H, m), 1.48-1.63 (3H, m), 1.25-1.31 (3H, m).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:28])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:10]1>C(Cl)Cl>[F:28][C:9]1([F:8])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(F)(F)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CCN(CC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 66 h
Yield: 83.8 %

Procedure:
TFA (766.5 mg, 517.9 μL, 6.722 mmol) was added to a stirred solution of tert-butyl 4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidine-1-carboxylate (2.046 g, 6.722 mmol) in DCM (15 mL) and the reaction stirred at ambient temperature for 66 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 50 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo to give the sub-title compound as a pale yellow solid (1.15 g, 84% Yield). 1H NMR (500 MHz, DMSO) δ 2.89 (dt, 2H), 2.82 (t, 2H), 2.64 (t, 2H), 2.42 (td, 2H), 2.32-2.09 (m, 4H), 1.67-1.58 (m, 2H), 1.52-1.44 (m, 1H), 0.95 (dtd, 2H); 19F NMR (471 MHz, DMSO) δ −90.80; LC-MS ES+: 205.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15](Br)=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25]>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>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:24]=[CH2:25])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCC1Oc2c(ccc(Br)c2CCCN)N1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1CCCN)OC(CC)N2C(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
A solution of N-t-butoxycarbonyl 7-(3-aminopropyl)-6-bromo-2-ethylbenzoxazole (396 mg, 1.03 mmol), vinyltributyltin (360 mg, 1.14 mmol), and tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.052 mmol) in toluene (10 mL) was refluxed for 3 hours. The crude reaction mixture was poured directly on a silica gel column, and the tin by-products were eluted with hexanes. The product was eluted with 25% EtOAc/hexanes to give a clear oil (180 mg, 53%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[CH3:28][C:29]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:30]=1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[F:38][C:35]1[CH:36]=[CH:37][C:29]([CH3:28])=[C:30]([CH:34]=1)[C:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)=[O:32]
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1C(=O)n1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 22.7 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.35 g) in dry pyridine (10 ml) and 2-methyl-5-fluorobenzoyl chloride (0.22 g), the title compound (0.11 g) was obtained as an amorphous pale yellow solid, MS, m/z: 490 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.S(=O)(=O)(O)O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: ClCc1coc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 g (6.43 mmol) of 4-chlorobenzamide is heated together with 816 mg of 1,3-dichloroacetone (6.43 mmol) at 135° C. for 1 h. The mixture is allowed to cool to RT, 1 ml of conc. sulphuric acid is added and the mixture is stirred for 5 min. The mixture is then poured onto ice, and the precipitate is filtered off with suction (946 mg). This precipitate is purified on 100 g of silica gel by column chromatography using a gradient of cyclohexane/ethyl acetate 20:1 to 5:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccccc2Cl)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4Cl)nnn3C)c2)nc1
Temperature: 120 °C
Yield: 75.6 %

Procedure:
A mixture of 4-(2-chlorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (322 mg, 1.24 mmol), methyl 6-chloronicotinate (213 mg, 1.24 mmol) and potassium carbonate (343 mg, 2.48 mmol) in DMF (7 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 30 to 100% ethyl acetate in heptane) afforded the title compound (370 mg, 76%) as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH2:14][CH:15]([CH2:21][O:22][C:23](=[O:26])[CH:24]=[CH2:25])[O:16][C:17](=[O:20])[CH:18]=[CH2:19])(=[O:12])[CH:10]=[CH2:11]>C(O)(=O)C>[CH3:1][N:2]([CH2:11][CH2:10][C:9]([O:13][CH2:14][CH:15]([O:16][C:17](=[O:20])[CH2:18][CH2:19][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:21][O:22][C:23](=[O:26])[CH2:24][CH2:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)OCC(COC(=O)C=C)OC(=O)C=C
Reactant: CNc1ccccc1
Solvent: CC(=O)O
Product: CN(CCC(=O)OCC(COC(=O)CCN(C)c1ccccc1)OC(=O)CCN(C)c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
Propoxylated glycerol triacrylate (GPTA—OTA 480, 5.08 g) was added to N-methylaniline (6.42 g—an equivalent amount required to react with the three acrylate groups, had the reactant been glycerol triacrylate) in glacial acetic acid (10 ml). The reaction mixture was heated at 100° C. for 2 hours and then the acetic acid removed by vacuum distillation. A portion of the residue (11 g) was then subjected to steam distillation to remove the excess N-methylaniline and the product extracted with dichloromethane (25 ml). The extract was dried over anhydrous magnesium sulphate, filtered and the dichloromethane removed by distillation in vacuo to leave a pale brown-coloured oil (6.46 g).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.Cl.[CH3:10][NH:11][O:12][CH3:13].C(N(CC)CC)C.CCCP(=O)=O>CN(C=O)C>[CH3:13][O:12][N:11]([CH3:10])[C:6]([CH:4]1[CH2:5][C:2](=[CH2:1])[CH2:3]1)=[O:8]
Reactant: CNOC
Reactant: C=C1CC(C(=O)O)C1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C1CC(C(=O)N(C)OC)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 3-methylenecyclobutanecarboxylic acid (525 mg, 4.68 mmol, Frontiers Scientific Services) in DMF (5 mL, aldrich) was added a solution of N,O-dimethyl hydroxylamine hydrochloride (0.55 g, 5.62 mmol, Aldrich) and triethylamine (0.78 mL, 5.62 mmol, Aldrich) in DMF (5 mL, Aldrich). The reaction was cooled to 0° C. and propylphosphonic anhydride solution (50 wt. % in DMF; 4.47 mL, 7.02 mmol, Alfa Aesar) was added. The reaction was stirred at RT for 16 h. The reaction was quenched with saturated NaHCO3 (10 mL) and stirred at RT for 5 min. The reaction was extracted with EtOAc (2×30 mL) and the combined organic extracts were washed with saturated ammonium chloride (2×40 mL), dried over MgSO4, and concentrated. The residue was dissolved in diethyl ether (5 mL) and the solution mixture was washed with H2O (2×10 mL), dried over MgSO4, concentrated, and dried in vacuo to give 398 mg of the title compound as a light yellow liquid. MS (ESI, positive ion) m/z: 156.1 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][CH2:27]O)[CH2:21]1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:27][CH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][O:20][CH2:21]1
Reactant: OCCC1CCCOC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCC1CCCOC1

Procedure:
A solution of triphenylphosphine (725 mg, 2.77 mmol) in DCM (4 ml) was added dropwise with water-bath cooling to a solution of 2-(tetrahydro-2H-pyran-3-yl)ethanol (300 mg, 2.304 mmol) and carbon tetrabromide (917 mg, 2.77 mmol) in DCM (6 ml).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>O1CCCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:15])[CH3:14]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
1.89 g of sodium hydride (60% content) was suspended in 23.76 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 23.79 g of a tetrahydrofuran solution containing 3.00 g of 2nitroaniline was dropwise added over 1 hour, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.41 g of acetic anhydride was added dropwise over 1 hr at room temperature and stirred for 2 hours. Then, water was added to the reaction mixture, and extraction and separation were conducted. The obtained organic layer was analyzed by high performance liquid chromatography to find the yield of the desired product was 84%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2ccc(OCCCBr)cc2N1
Yield: 88 %

Procedure:
7-hydroxy-3,4-dihydroquinolin-2(1H)-one (195 mg, 1.2 mmol), 1,3-dibromopropane (960 mg, 4.8 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 3) (300 mg, 88%) as a white solid. HPLC: 99%, RT 2.775 min. MS (ESI) m/z 284.0 [M+H]+.