Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:28][C@@:27]4([CH3:29])[C@@H:14]([CH2:15][CH2:16][C@@H:17]5[C@@H:26]4[CH2:25][CH2:24][C@@:22]4([CH3:23])[C@H:18]5[CH2:19][C@H:20]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C@@H:21]4[OH:30])[CH2:13][C@@H:12]3[OH:36])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:37]([Br:40])[CH:38]=[CH2:39]>>[Br-:40].[OH:36][C@@H:12]1[C@@H:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[CH2:28][C@@:27]2([CH3:29])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][C@H:20]([N+:31]3([CH2:39][CH:38]=[CH2:37])[CH2:32][CH2:33][CH2:34][CH2:35]3)[C@@H:21]2[OH:30])[CH2:13]1
Reactant: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: C=CCBr
Product: C=CC[N+]1([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCC7(CC6)OCCO7)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CCCC1
Product: [Br-]
Yield: 82 %

Procedure:
2β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-16β-(1-pyrrolidinyl)-5α-androstane-3α,17β-diol is reacted with allyl bromide as described in Example 5 to obtain the title compound in a yield of 82%, m.p.: 238°-240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH:14]([NH2:17])([CH3:16])C.[C:18]12[C:24](=CC=CC=1)[NH:23]C(=O)OC2=O>>[NH:17]1[CH2:14][CH2:16][N:23]=[C:24]1[CH2:18][NH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)NC(=O)c1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-isopropylbenzamide (prepared from isopropylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-isopropylbenzamide.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:20]=[N:19][C:18]2[C:17]3[S:21][C:22](Br)=[CH:23][C:16]=3[CH2:15][CH2:14][O:13][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1.C([Li])C[CH2:32][CH3:33].Cl[C:36]([O:38]CC)=[O:37]>CCCCCC>[Si:1]([O:8][CH2:9][C:10]1[C:20]([C:36]([OH:38])=[O:37])=[N:19][C:18]2[C:17]3[S:21][C:22]([CH2:32][CH3:33])=[CH:23][C:16]=3[CH2:15][CH2:14][O:13][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc2c(c1)OCCc1cc(Br)sc1-2
Reactant: CCOC(=O)Cl
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc2c(s1)-c1nc(C(=O)O)c(CO[Si](C)(C)C(C)(C)C)cc1OCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 3-tert-butyldimethylsilyloxymethyl-9-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (0.0500 g, 0.117 mmol;) in tetrahydrofuran (1.78 mL, 22.0 mmol) was added 1.60 M of n-butyllithium in hexane (0.0806 mL) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h. Ethyl chloroformate (0.0336 mL, 0.352 mmol;) was added to the mixture at −78° C. then let stirred 2 h. The reaction mixture was quenched with sat.NaHCO3 then extracted EtOAc (2×). The combined organic layers was dried Na2SO4, concentrated. The crude product was purified by flash chromatography (0-50% EtOAc/Hex) (eluted 15%) to give 3-tert-butyldimethylsilyloxymethyl-9-ethylcarboxy-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (36% yield). MS: (ESI+) 420.1
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(CCc2cccc3cncn23)cc1
Product: ClCc1ccc(CCc2cccc3cncn23)cc1

Procedure:
5-[p-(hydroxymethyl)phenethyl]imidazo[1,5-a]pyridine (2.52 g) is refluxed in 20 ml of thionyl chloride for 2 hours. Excess thionyl chloride is evaporated and the residue is partitioned between ethyl acetate and dilute sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated to yield 5-[p-(chloromethyl)-phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: [C:1]1([C:7](=[N:17][OH:18])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=O)[CH3:20]>>[CH3:19][C:20]1[O:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ccc(CC(=NO)c2ccccc2)cc1
Product: CSc1ccc(-c2c(-c3ccccc3)noc2C)cc1
Yield: 48 %

Procedure:
5-Methyl-4-[4-(methylthio)phenyl]-3-phenylisoxazole was prepared in 48% yield from the reaction of 1-phenyl-2-[4-(methylthio)phenyl]-ethan-1-one oxime (Step 2) and acetic anhydride according to the procedure outlined in Example 4, Step 1: Mass Spectrum: MH+=282. High resolution mass spectrum Calc'd. for C17H15NOS: 281.0874. Found: 281.0875. Anal. Calc'd. for C17H15NOS: C, 72.57; H, 5.37; N. 4.98; S, 11.39. Found: C, 72.56; H, 5.41; N, 5.00; S, 11.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:20])[CH:13](Cl)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:11][C:12](=[O:20])[CH:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(Cl)cc1)C(=O)OCC
Yield: 84.4 %

Procedure:
A mixture of 38.6 g (0.3 mole) of 4-chlorophenol, 70 g (0.36 mole) of diethylchloromalonate and 69.1 g (0.5 mole) of anhydrous potassium carbonate in 750 ml of acetone was heated at reflux for 48 hr, cooled, filtered and the filtrate concentrated. The residue was diluted with 250 ml of ethyl ether and was washed successively with two 100 ml portions of a 1% NaOH solution, once with H2O and once with brine, dried (sodium sulfate) and concentrated to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 72.6 g (84%) of white solid. An analytical sample, mp 43.5°-45° C. (lit. mp 58°-60° C.), was recrystallized from petroleum ether (60°-110° C.).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[NH:5]1)#[N:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O.O1CCCC1>[C:1]([N:3]=[C:4]1[NH:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[N:5]1[C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:2]
Reactant: COC(=O)C1=C(C)NC(=NC#N)NC1c1cccc(Cl)c1Cl
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1C(=NC#N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
A suspension of 2-(cyanoimino)-6-(2,3-dichlorophenyl)-3,6-dihydro-4-methyl-5-pyrimidinecarboxylic acid, methyl ester (444 mg, 1.31 mmoles) in dry dimethylformamide (2 ml) and tetrahydrofuran (2 ml) was cooled to 0° C. and was treated with triethylamine (0.5 ml) followed by ethyl chloroformate (284 mg, 2.62 mmoles). After the addition of ethyl chloroformate, the reaction turned yellow. The cooling bath was removed and stirring was continued at room temperature for 3 hours. The reaction was then diluted with ethyl acetate and washed with water, 5% citric acid, sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography (12% ethyl acetate in dichloromethane). The resulting product was crystallized from dichloromethane-isopropyl ether to provide 317 mg of the title compound as a colorless solid, melting point 176°-178° C.
Reaction SMILES: CO.[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:7][C:6](=[O:17])[C:5]=1[S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38]>CN(C)C=O>[CH2:35]([O:36][C:37](=[O:39])[CH2:38][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:7][C:6](=[O:17])[C:5]([S:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:4]([OH:3])[CH:9]=2)=[CH:15][CH:14]=1)[CH3:34]
Reactant: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCCc1ccccc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Reaction time: 3 h

Procedure:
To a methanol solution (3 ml) of the 4-hydroxy-6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (0.500 g, 1.47 mmol) was added cesium carbonate (0.955 g, 2.94 mmol). The reaction was stirred for 3 hrs. and is then concentrated in vacuo. Next, dimethylformamide (15 mL) is added and the residue is reconcentrated in vacuo to dryness. The solid is then diluted with dimethylformamide (3 mL) and bromoethylacetate (0.491 mL, 2.94 mmol) is added. The slurry is then stirred for 3 hrs. The reaction is quenched by dilution with ethyl acetate (100 mL). The organic layer is washed in succession with; 1N HCl, water, saturated sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (SiO2 --230 to 400 mesh) using a gradient of 15% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to 30% ethyl acetate/30% hexanes/40% methylene chloride.: m.p. 169°-171° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, 3 H), 2.75 (t, 2 H), 2.96 (t, 2 H), 4.16 (q, 2 H), 4.87 (s, 2 H), 6.69 (s, 1 H), 7.06 (d, 2 H), 7.19 (m, 5 H), 7.73 (d, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[OH:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Reactant: COc1ccccc1-c1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(O)(c2ccccc2)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Reaction time: 1 h
Yield: 16.9 %

Procedure:
A solution of 3′-bromo-2-methoxybiphenyl (1.08 g, 4.1 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. and 2.5M n-butyllithium in hexanes (1.64 mL, 4.1 mmol) was added at such a rate that the temperature did nor exceed −70° C. Stirring was continued at −78° C. for 1 hr. A solution of 25 (1.5 g, 4.1 mmol) in tetrahydrofuran (6 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 20 min and at room temperature for 2 hr. The reaction mixture was poured onto saturated ammonium chloride (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (4 L). Pure 26 (0.87 g) and slightly impure 26 (0.38 g) were isolated (total yield 55%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C.O>[CH2:27]([O:19][C:5]1[CH:4]=[C:3]([O:20][CH2:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(=O)c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
1-(5-Chloro-2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) was dissolved in acetonitrile and potassium carbonate (4 eq) was added portion wise. The suspension was stirred for five minutes, before the addition of benzyl bromide (2.4 eq), and after which, the reaction mixture was stirred under nitrogen at reflux for 3 hours. The reaction was allowed to cool to room temperature and diluted with water. This was extracted into ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a syrup. This was triturated with 1:1 diethyl ether:hexane to give 1-(2,4-bis-benzyloxy-5-chloro-phenyl)-2-(4-methoxy-phenyl)-ethanone as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.S(Cl)([Cl:11])=O.[CH3:13][OH:14]>>[ClH:11].[CH3:13][O:14][C:3]([C@H:4]1[CH2:7][C@@H:1]([NH2:2])[CH:6]=[CH:5]1)=[O:8]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C1NC2C=CC1C2
Product: COC(=O)[C@@H]1C=C[C@H](N)C1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(−)-2-Azabicyclo[2,2,1]hept-5-en-3-one (20.00 g, 0.1833 mmol) was dissolved in MeOH (140 mL) and this mixture was cooled to 0° C. Thionyl chloride (29.4 mL, 0.403 mol) was then added dropwise, keeping the temperature less than 15° C. Upon completion of addition, the mixture was left to stir at 5° C. for 2 hours. The solvent was removed under reduced pressure to yield an oil, which was dried further under high vacuum overnight at 35° C. to afford the title compound as a white solid (33 g) which was used without further purification. 1H NMR (300 MHz, DMSO, δ): 8.45 (s, 3H), 6.03 (m, 1H), 5.87 (m, 1H), 4.13 (m, 1H), 3.60 (m, 4H), 2.53 (m, 1H) and 1.89 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:19]([CH3:30])[C:20]([C:28]#[N:29])=[C:21]2[C:25]=1[O:24][C:23]([CH2:26][OH:27])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:19]([CH3:30])[C:20]([C:28]#[N:29])=[C:21]3[C:25]=2[O:24][C:23]([CH2:26][OH:27])=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(CO)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(CO)nc2c1C#N
Temperature: 95 °C
Reaction time: 3 h
Yield: 11.1 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (18.2 μl, 0.143 mmol) and triethylamine (26.7 μl, 0.191 mmol) were added to a dimethyl sulfoxide (0.5 ml) solution of 7-fluoro-2-hydroxymethyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-218) (27.0 mg, 0.096 mmol), followed by stirring in an oil bath at 95° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (10 ml), and washed with saturated brine (10 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol-10:1), and the eluate was purified in slurry with diethyl ether to obtain the entitled compound (4.00 mg, 11.1%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH2:15][CH3:16])[C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH:18]1([CH2:21][O:22][CH:23]2[CH2:29][CH:28]3[NH:30][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:18]1([CH2:21][O:22][CH:23]2[CH2:24][CH:25]3[N:30]([CH2:2][CH2:3][CH2:4][N:5]4[C:10]5[CH:11]=[CH:12][CH:13]=[C:14]([CH2:15][CH3:16])[C:9]=5[O:8][CH2:7][C:6]4=[O:17])[CH:28]([CH2:27][CH2:26]3)[CH2:29]2)[CH2:20][CH2:19]1
Reactant: C1CC1COC1CC2CCC(C1)N2
Reactant: CCc1cccc2c1OCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cccc2c1OCC(=O)N2CCCN1C2CCC1CC(OCC1CC1)C2
Temperature: 60 °C
Reaction time: 90 h
Yield: 20.6 %

Procedure:
A 7 ml vial was charged with 4-(3-chloropropyl)-8-ethyl-4H-benzo[1,4]oxazin-3-one (0.21 g, 0.83 mmol), 3-cyclopropylmethoxy-8-aza-bicyclo[3,2,1]octane (0.16 g, 0.87 mmol), K2CO3 (0.23 g, 1.7 mmol), acetonitrile (4 ml) and shaken at 60° C. for 90 hours The reaction mixture was evaporated to dryness and purified by prep TLC (SiO2; heptanes/EtOAc 1:1) followed by Prep HPLC to give the title compound (0.068 g, 20.5%). 1H NMR (CDCl3) 1H NMR (CDCl3) δ 7.05-6.84 (m, 3H), 4.56 (s, 2H), 4.04-3.98 (m, 2H), 3.53-3.49 (m, 1H), 3.19-3.11 (m, 4H), 2.67-2.59 (m, 2H), 2.42-2.37 (m, 2H), 2.07-1.74 (m, 10H), 1.21-1.15 (m, 3H), 1.06-0.93 (m, 1H), 0.51-0.44 (m 2H), 0.21-0.14 (m, 2H); 13C NMR (CDCl3) δ 164.60, 143.25, 133.02, 128.66, 123.99, 122.32, 113.20, 72.78, 72.23, 67.74, 58.59, 49.56, 39.83, 35.73, 26.45, 26.17, 23.03, 14.50, 11.04, 2.94.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([O:12][C:11](=[O:13])[NH:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]2=3)[CH2:4][CH2:3]1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25]([C:27]2[CH:36]=[C:35]([CH3:37])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:20]=1.[CH3:38]CN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][N:31]1[C:30]2[C:35]([CH3:37])=[CH:36][C:27]([C:25]([C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:2]4[CH2:3][CH2:4][C:5]5([O:12][C:11](=[O:13])[NH:10][C:9]6[CH:14]=[CH:15][CH:16]=[CH:17][C:8]5=6)[CH2:6][CH2:7]4)[CH:20]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC4(CC3)OC(=O)Nc3ccccc34)ncn2)cc2oc(=O)n(C)c12
Reaction time: 48 h

Procedure:
102 mg (0.400 mmol) spiro[benzo[d][1,3]oxazin-4,4′-piperidin]-2(1H)-on hydrochloride, 122 mg (0.400 mmol) 6-(6-chloropyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.210 mL (1.20 mmol) DIPEA were combined in 3.0 mL DMF and stirred for 48 h. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i.vac. and the aqueous phase remaining was neutralised with 4M aqueous NaOH solution. The product precipitated as a solid was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O-])=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[Li+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:36]2[CH:37]=[CH:38][CH:39]=C[C:35]=2[N:34]=[N:33]1.NN1CCCCC1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([C:13]([NH:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C([O-])C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NN1CCCCC1)C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
Part B: A mixture of the crude lithium 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (1.0 gram, ˜0.0027 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.2 gram, 0.0027 mol), 1-aminopiperidine (0.3 gram, 0.003 mol) and triethylamine (1 ml) in DMF (30 ml) is stirred at room temperature for 16 hours. After concentration in vacuo, water is added and the resulting mixture is extracted (2×) with dichloromethane. The dichloromethane layers are collected, dried over MgSO4, filtered and concentrated in vacuo to give a residue that is further purified by flash chromatography (silicagel, dichloromethane/methanol=95/5 (v/v)) to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihydro-1H-imidazole-4-carboxamide (380 mg, 31% yield). Melting point: 113-116° C. 1H-NMR (200 MHz, CDCl3): δ 1.33-1.48 (m, 2H), 1.60-1.80 (m, 4H), 2.68-2.82 (m, 4H), 4.28-4.35 (m, 2H), 4.84 (dd, J=11 and 9 Hz, 1H), 6.65 (br d, J=8 Hz, 2H), 7.11 (br d, J=8 Hz, 2H), 7.23-7.33 (m, 2H), 7.41 (d, J=2 Hz, 1H), 7.57 (br s, 1H).
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.C([O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:29])[NH2:28])[CH:22]=1)(C)(C)C.[C:31](O)(=O)C>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:4]([CH3:31])=[CH:3][N:28]=[C:27]([C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[C:20]([OH:19])=[O:30])[N:29]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=N)N)c1
Reactant: CC(=O)O
Reactant: CN(C)CCC(=O)c1ccc(F)cc1
Product: Cc1cnc(-c2cccc(C(=O)O)c2)nc1-c1ccc(F)cc1
Temperature: 130 °C
Yield: 12 %

Procedure:
Part B. A mixture of 3-dimethylamino-1-(4-fluoro-phenyl)-propan-1-one (641.9 mg, 3.10 mmol) and 3-carbamimidoyl-benzoic acid tert-butyl ester (426.1 mg, 1.91 mmol) in anhydrous acetic acid (8 mL) is heated to 130° C. at 300 W, 250 psi in a microwave reactor for 30 min. A white solid is precipitated by addition of 1 N HCl, and collected by filtration, followed by washing with water and hexanes. The obtained solid is further purified by flash column chromatography, eluting with methanol/methylene chloride (1:40) to afford the title product (114.1 mg, 12.0% yield), m.p. 272-275° C. 1H NMR (300 MHz, DMSO-d6): δ 8.50 (2H, d, J=8.0 Hz), 8.06 (2H, d, J=8.0 Hz), 7.85 (2H, m), 8.13 (2H, m), 7.38 (2H, m), 2.40 (3H, s). MS (ES+): m/e 309.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[C:4]([F:19])[C:3]=1[N+]([O-])=O.[H][H].O.[CH:26]([OH:29])(C)C>O=[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[C:4]([F:19])[C:3]=1[O:29][CH3:26]
Reactant: [H][H]
Reactant: CC(C)O
Reactant: CCCCC[C@H]1CC[C@H](c2cc(F)c([N+](=O)[O-])c(F)c2)CC1
Agent: O=[Pt]=O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](c2cc(F)c(OC)c(F)c2)CC1
Reaction time: 0.5 h

Procedure:
31.1 g of 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-nitrobenzene is dissolved in 450 ml of isopropanol and hydrogenated over 0.5 g of PtO2 at 20° and under normal pressure until the calculated quantity of hydrogen has been taken up. The solution is filtered and evaporated. The resulting crude, 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-aniline is dissolved in a mixture of 25 ml of concentrated sulfuric acid, 75 ml of dioxane and 75 ml of water and is diazotized at 3° to 6° with a solution of 8 g of NaNO2 in 15 ml of water. The mixture thus obtained is introduced in portions while stirring into 500 ml of boiling water. The mixture is boiled for a further 30 minutes and cooled and the resulting 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenol is filtered off and dissolved in 250 ml of 1N sodium hydroxide solution. 12.6 g of dimethyl sulfate is added in portions and the mixture is then heated at 100° for 1 hour. Cooling and working up in the usual manner gives 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-anisole.