Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[C:17]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:4][CH:3]([OH:5])[C:2]([F:7])([F:6])[F:1])[CH2:31][CH2:30]3)=[O:28])[C:17]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:16]2)=[CH:13][CH:14]=1
Reactant: FC(F)(F)C1CO1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(O)C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
1,1,1-trifluoro-2,3-epoxypropane (9 uL, 0.10 mmol) was added to a mixture of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[piperazin-1-yl]-methanone (30 mg, 0.048 mmol) and triethylamine (20 uL, 0.144 mmol) in anhydrous methanol (1.0 mL). The reaction was stirred overnight. Evaporation of the solvent and chromatography of the residue over silica gel using 0-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-trifluoromethyethyl)-piperazin-1-yl]-methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-trifluoromethyethyl)-piperazin-1-yl]-methanone hydrochloride as an off-white powder (38 mg, 84%). LR-MS (APCI): 703.5 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[CH:28]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:43])[CH2:38][CH2:39][CH2:40][C:41]#[CH:42])[CH2:33][CH2:32]1)([CH3:30])[CH3:29]>C(NCC)C.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.[Cu](I)I>[CH:28]([N:31]1[CH2:32][CH2:33][N:34]([C:37](=[O:43])[CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:2]2[CH:3]=[CH:4][N:5]3[C:10]=2[C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH3:19])=[N:6]3)[CH2:35][CH2:36]1)([CH3:30])[CH3:29]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Reactant: C#CCCCC(=O)N1CCN(C(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)CC1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
A mixture of (S)-tert-butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (140 mg, 0.32 mmol), 1-(4-isopropylpiperazin-1-yl)hex-5-yn-1-one (88 mg, 0.36 mmol), bis(triphenylphosphine)palladium(II) chloride (23 mg, 0.03 mmol) and copper iodide (6 mg, 0.03 mmol) in diethylamine (6 ml) was heated at 60° C. for 3 days. The solvent was removed and the crude purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 134 mg (72% yield) of the title compound. Purity 100%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25](F)=[C:24]([F:29])[CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:29][C:24]1[CH:23]=[C:22]([S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:20])=[O:21])[CH:27]=[CH:26][C:25]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(O)cc(O)c1
Product: O=C(O)Cc1cc(O)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The subtitle compound was prepared as described in example 2 step (iii) but instead using 3,5-dihydroxyphenylacetic acid and the product from example 24 step (i).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([Cl:32])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:23]=1)[O:14][C:15]([N+:20]([O-:22])=[O:21])([CH3:19])[C:16](O)=[O:17].CN(C)C=O.C>ClCCCl>[Cl:32][C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:6]([Cl:5])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:23]=1)[O:14][C:15]([N+:20]([O-:22])=[O:21])([CH3:19])[C:16]([Cl:3])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)O)[N+](=O)[O-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)Cl)[N+](=O)[O-]
Yield: 84 %

Procedure:
9.7 g (82 mmol) of thionyl chloride were added dropwise to a solution of 30 g (68 mmol) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-α-phenoxy-propionic acid and 0.5 ml of dimethylformamide in 100 ml of 1,2-dichloroethane at room temperature. The mixture was heated under reflux for 4 hours. Active charcoal was added, the mixture was filtered and the filtrate was concentrated. After digesting the oily residue with 100 ml of ligroin, 26.2 g (84% of theory) of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-α-phenoxy-propionyl chloride were obtained in the form of yellow crystals of melting point 92° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH:23][C:24]([CH3:29])([CH3:28])[C:25](O)=O>>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:25]([C:24]([OH:23])([CH3:29])[CH3:28])=[N:22][C:16]=2[CH:17]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCNCC1

Procedure:
2-(5-Methyl-1-piperidin-4-yl-1H-benzoimidazol-2-yl)-propan-2-ol was prepared from 4-(2-amino-4-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester and 2-hydroxyisobutyric acid according to the procedure described by Skolnik et. al. J. Amer. Chem. Soc., 1943, 65, 1854-1858. The yields of the product after washing with water and drying varied from 78-87% as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 7.60, 7.36, 6.99, 5.63 (s, 1H), 5.30 (m, 1H), 3.10 (br m, 2H), 2.54 (br m, 2H), 2.37 (s, 3H), 2.22-2.36 (m, 3H), 1.74 (brd, 2H), 1.61 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2([C:28]([OH:30])=O)[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2([C:28]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=3)=[O:30])[CH2:27][CH2:26]2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)cc3)c2cc1OC
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)NCc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylic acid (74.3 mg, 0.182 mmol), 4-Fluoro benzylamine (25 μL, 0.219 mmol), DIEA (90.0 μL, 0.544 mmol) in DMA (1.0 mL) was added HATU (203 mg, 0.534 mmol). The resulting solution was stirred at room temperature for 1 hour before adding dropwise to water (10 mL) with stirring. The slurry was sonicated, filtered and the solids were washed with 1N NaOH followed by water. After air drying, the solids were further purified by prep HPLC, affording ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[(4-fluorophenyl)methyl]cyclopropane-1,1-dicarboxamide (33 mg, 35% yield, 98% pure) as a white solid. 1H NMR (DMSO, d6): 10.82 (s, 1H), 8.80 (d, 1H), 8.50 (t, 1H), 7.83 (d, 2H), 7.74 (s, 1H), 7.56 (s, 1H), 7.30-7.38 (m, 4H), 7.15 (t, 2H), 6.80 (d, 1H), 4.32 (d, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 1.42 (s, 4H).
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].CO>ClCCl>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH2:6]1
Reactant: CC(=O)OC1CCN(CC#CCN2CCCC2=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCN1CC#CCN1CCC(O)C1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A mixture of 800 mg of (racemic)-1-[4-[3-(acetyloxy)-1-pyrrolidinyl]-2-butynyl]-2-pyrrolidinone, 595 mg of sodium carbonate and 40 ml of methanol was stirred overnight. An equal volume of dichloromethane was added and this mixture was filtered. The filtrate was concentrated and the residue was diluted with dichloromethane, filtered and concentrated in vacuo. The residue was purified by chromatography (alumina), giving 470 mg of the desired product as a pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH2:30][C:31]([CH3:37])([OH:36])[CH2:32][CH2:33][CH2:34][OH:35]>>[CH3:37][C:31]([OH:36])([CH2:30][NH:29][CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2)[CH2:32][CH2:33][CH2:34][OH:35]
Reactant: CC(O)(CN)CCCO
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC(C)(O)CCCO)n(C)c2n1

Procedure:
Following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 5-amino-4-methylpentane-1,4-diol were reacted to give 410. [M+H]+ 495.6
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1>Cl.O1CCOCC1>[N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
The title compound from Step B above (50 mg, 0.2 mmol) was dissolved in 4 M HCl in dioxane (2.0 mL) and stirred at RT for 1 h. The product was concentrated under reduced pressure and dried under high vacuum to give the title compound (i-17) (30 mg, 96%). ESI-MS calculated for C8H13N3: Exact Mass: 151.11. Found 152.10.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: CCCCCC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Solvent: CC#N
Product: CCCCCC(=O)Nc1c(C)cc(Br)cc1C
Temperature: 150 °C
Yield: 50 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (0.50 g) and hexanoyl chloride (0.45 mL) were dissolved in acetonitrile (4 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo and purified by flash chromatography to furnish 0.37 g (50% yield) of the title compound as a white solid. LC-MS (m/z) 299 (MH+); tR=3.09, (UV, ELSD) 100%, 99%. 1H NMR (500 MHz, CDCl3): 0.93 (t, 3H), 1.39 (m, 4H), 1.76 (qui, 2H), 2.20 (s, 6H), 2.40 (t, 2H), 6.57 (b, 1H), 7.23 (s, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:21]4=[N:22][C:23](I)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:45]2[CH:50]=[CH:49][C:48]([C@H:51]3[CH2:56][CH2:55][C@H:54]([OH:57])[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)O1>>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:21]4=[N:22][C:23]([C:45]5[CH:50]=[CH:49][C:48]([C@H:51]6[CH2:52][CH2:53][C@H:54]([OH:57])[CH2:55][CH2:56]6)=[CH:47][CH:46]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(I)nc2n1COCC[Si](C)(C)C
Reactant: CC1(C)OB(c2ccc([C@H]3CC[C@H](O)CC3)cc2)OC1(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C

Procedure:
The title compound is prepared from 2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-5-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine and (trans)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanol following a procedure analogous to that described for Intermediate 7 Step 2. LC (method 5): tR=1.16 min; Mass spectrum (ESI+): m/z=716 [M+H]+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([NH2:30])[CH3:29])=[CH:20][CH:19]=1.CCO.CC#N>C(O)(C(F)(F)F)=O>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([NH:30][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH3:29])=[CH:20][CH:19]=1
Reactant: CC(N)CCCCCOc1ccc(Cl)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(CCCCCOc1ccc(Cl)cc1)Nc1c(Nc2cccnc2)c(=O)c1=O
Yield: 12 %

Procedure:
The title compound was prepared from 3-ethoxy-4-(pyridine-3-yl-amino)-3-cyclobutene-1,2-dione (164 mg, 0.75 mmol) prepared according to example 1A and crude 6-(4-chlorophenoxy)-1-methyl-hexylamine (738 mg) in refluxing EtOH (15 ml). After 36 h the solvent was evaporated and the product was isolated by preparative HPLC chromatography using a gradient of 30 to 50% MeCN in 0.01% aq. TFA and subsequent freeze drying of the product containing fractions.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:39])[O:5][C:6]1[CH:7]=[C:8]([CH:25]=[C:26]([C:28]2[NH:29][C:30]([C:33]3[O:34][C@@H:35]([CH3:38])[CH2:36][N:37]=3)=[CH:31][CH:32]=2)[CH:27]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])=[N:14][CH:15]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:38][C@@H:35]1[O:34][C:33]([C:30]2[NH:29][C:28]([C:26]3[CH:27]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[CH:15]=[N:14][C:13]([C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)=[O:17])=[CH:12][CH:11]=4)[CH:25]=3)[O:5][C@@H:4]([CH3:39])[CH2:3][OH:2])=[CH:32][CH:31]=2)=[N:37][CH2:36]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCN(C)CC3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ccc(C(=O)N5CCN(C)CC5)nc4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Reaction time: 0.83 h
Yield: 28 %

Procedure:
1-{[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridin-2-yl]carbonyl}-4-methylpiperazine (185 mg, 0.35 mmol) synthesized in Example (129g) was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 694 μL, 0.694 mmol) was added at −78° C. Subsequently, the temperature was brought back to room temperature, followed by stirring for 50 minutes. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-10%) to afford the desired compound (51 mg, yield 28%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[N:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[N:12][NH:13][C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1c2n[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2n[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CCCC3

Procedure:
To 2-(4-chlorophenyl)-2,5-dihydropyrazolo[4,3-c]cinnolin-3-one (0.5 g) dissolved in trifluoroacetic acid (20 ml) was added platinum oxide (0.2 g). The re action mixture was hydrogenated at 50 psi until no further uptake of hydrogen was observed. The catalyst was collected by filtration, the filtrate was poured onto ice and basified with ammonia. On the addition of dichloromethane a solid precipitated out; the solid was collected by filtration, washed with water and dried. Recrystallisation from ethanol gave the title compound. δH (360 MHz; DMSO-d6) 1.83 (4H, m, CH2), 2.67 (2H, t, J=5.7 Hz, CH2), 2.75 (2H, t, J=5.7 Hz, CH2), 7.51 (2H, d, J=9 Hz, ArH), 8.23 (2H, d, J=9 Hz, ArH), m/z (ESP+) 301/303 (MH+).
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O.CC(C)=O>O>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 11 h

Procedure:
1 g of 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (8.70 mmoles) is dissolved in 1 ml water. 1.5 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (9.48 mmoles) are added and the mixture is heated at 50° for 11 h with stirring by a magnetic stirrer. Heating is then continued at the boiling point for a further 11 h. The mixture is cooled, 10 ml acetone is added, stirring is performed for 30 min and the mixture is filtered. The product obtained is crystallised from methanol to give oxiractam of m.p. 167°-70° C. as a white crystalline powder.
Reaction SMILES: [CH:1](/[C:9]1[N:13]=[CH:12][O:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>C(O)C.[Hg]>[CH:1](/[C:9]1[N:13]=[CH:12][O:11][N:10]=1)=[CH:2]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C(=C/c1ncon1)\c1ccccc1
Agent: [Hg]
Solvent: O
Solvent: CCO
Product: C(=C\c1ncon1)\c1ccccc1

Procedure:
3-(trans-Styryl)-1,2,4-oxadiazole (0.75 g.) in absolute ethanol (750 ml.) was irradiated at room temperature, under nitrogen for a total of 31 hr. using a medium pressure mercury vapour arc tube contained in a water cooled glass well immersed in the solution. The ultraviolet spectra of suitably diluted aliquots showed a reduction in the intensity of absorption at ca. 274 nm over the period of irradiation. The colourless solution was evaporated to a low volume when the trans isomer (0.11 g.), m.p. 84° , λmax. (EtOH) 274 nm (ε 26,200) separated. Evaporation of the mother liquors to dryness gave a solid and an oil. The oil was separated and thoroughly dried to give 3-(cis-styryl)-1,2,4-oxadiazole contaminated with ca. 25% by weight of the trans-isomer, λmax. (EtOH) 272-273 nm (ε 14,300), pmr. shows cis-protons at 2.92 and 3.50 (J = 12.5) and confirms the presence of the transisomer.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: N#Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C#N)c1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 1H-Imidazole-4-carbonitrile (300 mg, 3.22 mmol) and 4-Fluoro-3-methoxynitrobenzene (552 mg, 3.22 mmol) in DMF (Volume: 6446 μl) was added K2CO3 (891 mg, 6.45 mmol). The resulting mixture was brought to 120° C. and stirred overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbonitrile (698 mg, 2.86 mmol, 89% yield). LC-MS (M+H)+=245.0. 1H NMR (500 MHz, MeOD) δ ppm 8.30-8.34 (1H), 8.19-8.23 (1H), 8.09-8.12 (1H), 8.00-8.05 (1H), 7.71-7.79 (1H), 4.02-4.10 (3H).
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C[Zn]C.[C:27]([O:30][C:31](=[O:33])[CH3:32])(=O)[CH3:28].[C:34]1(=O)[CH2:48][CH2:47]C[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=[CH:35]1.S(=O)(=O)(O)O>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1(C)C=CC=CC=1>[C:31]([O:30][C:27]1[CH2:47][CH2:48][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]([CH3:45])[CH:28]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CCCCCCCCCCCCC1
Agent: [Cu+2]
Agent: C[Zn]C
Agent: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1=CC(C)CCCCCCCCCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Placed in a 2000-mL flask equipped with a stirrer, dropping funnel and thermometer were 54.3 mg (0.15 mmol) of Cu(OTf)2, 25 g of toluene and 93.1 mg (0.30 mmol) of triphenyl phosphate, and the inner atmosphere was replaced with nitrogen. After replacement with nitrogen, the mixture was stirred at 25° C. for 20 min. Then, 9 mL (18 mmol) of a toluene solution (2.0 mmol/L) of dimethylzinc was added to the mixture at 25° C., followed by further stirring for 10 min. The mixture was then cooled to −17° C., followed by addition of 1.68 g (16.5 mmol) of acetic anhydride, and 3.34 g (15 mmol) of 2-cyclopentadecenone was added dropwise to the mixture over the period of 1 hour. After completion of the dropwise addition, stirring was continued at the same temperature for 6 hours. After the reaction was completed, 32.5 g of a 5% aqueous sulfuric acid solution as cooled to 0° C. was added to the reaction mixture for quenching. After separation, the organic layer was washed with water (5 times), and the resultant organic layer was concentrated under reduced pressure to give 4.93 g of a crude product. The crude product was purified by silica-gel column chromatography to produce 3.89 g (13.8 mmol, 92% yield) of dl-3-methycyclopentadecene-1-yl acetate.