Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:23])([F:22])[CH2:4][NH:5][C:6]([CH3:21])([CH3:20])[C:7](=[N:18][OH:19])[CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[N+:15]([O-:17])=[O:16].C(N(CC)C(C)C)(C)C.Cl[C:34]([CH3:40])([CH3:39])[CH:35]([N:37]=[O:38])[CH3:36]>C(#N)C>[F:23][C:3]([F:22])([CH2:4][NH:5][C:6]([CH3:21])([CH3:20])[C:7](=[N:18][OH:19])[CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[N+:15]([O-:17])=[O:16])[CH2:2][NH:1][C:34]([CH3:40])([CH3:39])[C:35](=[N:37][OH:38])[CH3:36]
Reactant: CC(C)(NCC(F)(F)CN)C(CCn1ccnc1[N+](=O)[O-])=NO
Reactant: CC(N=O)C(C)(C)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=NO)C(C)(C)NCC(F)(F)CNC(C)(C)C(CCn1ccnc1[N+](=O)[O-])=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A clear solution of 4-(3-amino-2,2-difluoropropylamino)-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-pentanone oxime (title B compound) (0.40 g, 1.20 mmol) and N,N-diisopropylethylamine (0.42 g, 3.32 mmol) in acetonitrile (5 mL) was treated with 3-chloro-3-methyl-2-nitrosobutane (prepared analogously to 3-chloro-3-methyl-2-nitrosobutane, Example 1, step (B)) (0.45 g, 3.32 mmol) with stirring at room temperature under nitrogen atmosphere for 2 hours. After evaporation of the solvent under vacuum, the paste thus obtained was loaded, as a powder adsorbed on silica gel, onto a silica gel column and eluted with methanol-dichloromethane (2:98). The fractions with compound were pooled together and evaporated to afford the title product, which was further purified by crystallization from CH2Cl2—CH3OH to a cream colored solid. Yield: 0.45 g (88%); mp. 90-92° C.; 1H NMR (DMSO-d6) d, 1.12 [s, 12H, C(CH3)2 ], 1.70[s, 3H, C(=NOH)CH3], 2.18 & 2.22(2t, 2H, NH), 2.62(m, 4H, CH2CF2), 2.80(t, 2H, J=7.25 Hz, CH2CH2N), 4.61(t, 2H, J=7.25 Hz, CH2CH2N), 7.15 & 7.52 (2s, 2H, imi-H) and 1.046 & 10.90(2s, 2H, NOH). MS m/e 434 (M+H)+. Anal. Calcd for C17H29N7O4F2: C, 47.11; H, 7.74; N, 22.62; F, 8.77. Found: C, 47.28; H, 6.54; N, 22.79; F, 8.53. HPLC: Retention time: 20.74 min [Microsorb-C18, 0.46×25 cm, 5 m; solvent: 0.1% trifluoroacetic acid (TFA)/water (A) and 0.1% TFA/acetonitrile (B); flow rate: 1.0 mL/min.; run condition: linear gradient, 1% increase in B per min.; ran at 230 and 254 nm for 50min.; in both cases a single peak was observed; 98.95% (230 nm) and 100% (254 nm)].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([F:36])[CH:30]=1)([CH3:25])=[O:27]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: CP(C)(=O)c1ccc(N)c(F)c1
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2F)ncc1C(F)(F)F

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(dimethylphosphoryl)-2-fluoroaniline.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[O:24][CH:23]=[C:22]([CH:25]=[O:26])[CH:21]=1>O1CCCC1>[OH:26][CH:25]([C:22]1[CH:21]=[C:20]([Si:19]([CH3:28])([CH3:27])[CH3:18])[O:24][CH:23]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCCCCCCCCc1ccccc1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)CCCCCCCCCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 9-phenylnonylmagnesium bromide (1.35 mmol, prepared from 0.383 g, 1.35 mmol of 1-bromo-9-phenylnonane and 4.11 mmol magnesium) in tetrahydrofuran (5 ml) at 0° under argon was added dropwise, 5-trimethylsilyl-3-furaldehyde (0.227 g, 1.35 mmol) in tetrahydrofuran (3 ml). The solution was warmed to room temperature and stirred for 30 minutes, quenched with 5% ammonium chloride and extracted into ethyl ether. The organic portion was washed with saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Purification by flash chromatography (silica, 5 to 20% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH3:18])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[C:29]([CH3:36])=[N:28]1>ClCCl>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[S:32]([C:30]3[C:29]([CH3:36])=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Cc1nn(C)cc1S(=O)(=O)Cl
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)cc1S(=O)(=O)N(C)CCN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine hydrochloride salt (0.5 g, 1.29 mmol) in dichloromethane (10 ml) and cool in an ice-bath. Add triethylamine (0.90 ml, 6.44 mmol) and then 1,3-dimethylpyrazole-4-sulfonyl chloride (250 mg, 1.29 mmol). Remove the ice-bath and allow to warm to ambient temperature and allow to stir for 2 hr. Wash the organic phase with aqueous sodium bicarbonate, brine and water. Dry over sodium sulfate and concentrate. Purify by chromatography, eluting with 1:2 hexanes:acetone to afford the title preparation (535 mg, 100% yield) as a white foam. MS ES: m/z=414 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)C.[NH3:13]>CO>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([NH2:13])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1csc(N)n1
Yield: 95 %

Procedure:
A solution of 2.5 g (15.0 mmol) (2-Amino-thiazol-4-yl)-acetic acid ethyl ester in 70 ml of 7N ammonia solution in methanol was stirred for 6 days at room temperature. After concentration in vacuo, one obtains 2.0 g (95%) of the title compound as a light brown solid, which was directly used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1.C([O:16][CH:17](O)[C:18]([F:21])([F:20])[F:19])C.O>C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[CH:17]([C:12]1[N:7]=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=1)[OH:16]
Reactant: CCOC(O)C(F)(F)F
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(C(O)C(F)(F)F)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 19.2 %

Procedure:
Potassium carbonate (4.66 g, 36.3 mmol) was added to the mixture of pyridin-3-ol (2.00 g, 21.0 mmol) and 1-ethoxy-2,2,2-trifluoroethanol (3.30 g, 23.1 mmol), and the mixture was stirred for 4 hours at 100° C. under nitrogen atmosphere. This reaction solution was cooled to room temperature, followed by adding water and ethyl acetate to the reaction solution, washing the organic layer with a saturated saline solution, drying the layer with anhydrous sodium sulfate, and thereafter concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (Purif-Pack SI200, hexane:ethyl acetate:=40:60) to obtain the title compound (780 mg, yield: 19%) as a white amorphous.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)C=CC=CC=1.[H-].[Na+].[CH2:35]([N:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CS(C)=O>[CH2:35]([N:42]1[CH2:47][CH2:46][C:45](=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: FC(F)(F)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)Oc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Triphenyl-(4-trifluoromethoxybenzyl) phosphonium bromide (21.6 g, 41.75 mmol) was dissolved in DMSO (110 ml), to which sodium hydride (1.82 g, 45.52 mmol) was added, and the mixture was stirred for 30 minutes. 1-Benzyl-4-piperidone (7.18 g, 37.96 mmol) was added to the mixture, and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) to afford 1-benzyl-4-(4-trifluoromethoxybenzylidene)piperidine (9.75 g, yield 74%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][O:14][CH2:15]3)[N:3]=1.CI.[C:21]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:21])=[C:4]([N:11]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(N2C3CCC2COC3)c2nc[nH]c2n1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cnc2c(N3C4CCC3COC4)nc(Cl)nc21
Reaction time: 65 h
Yield: 98.2 %

Procedure:
A mixture of 2-chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine (650 mg, 2.45 mmol), methyl iodide (183 μL, 2.94 mmol) and K2CO3 (473 mg, 3.43 mmol) in THF (15 mL) was stirred at r.t. for 18 h before further methyl iodide (50 μL, 0.80 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (673 mg, 98%). LCMS (method H): RT 2.63 min [M+H]+ 280.3
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=3[CH3:20])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:23][NH2:24].C1C(O)=CC(C(O)=O)=C(O)C=1>O1CCOCC1>[CH3:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([N:10]1[CH2:9][CH2:8][C:5]2[N:6]=[N:7][C:2]([NH:23][NH2:24])=[CH:3][C:4]=2[CH2:11]1)=[O:21]
Reactant: Cc1cccc(C(=O)N2CCc3nnc(Cl)cc3C2)c1C
Reactant: NN
Agent: O=C(O)c1cc(O)ccc1O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C(=O)N2CCc3nnc(NN)cc3C2)c1C

Procedure:
10.3 g of 3-chloro-6-(2,3-dimethylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 50 cc of hydrazine hydrate in 80 cc of dioxane are heated in an oil bath of 80°. After a reaction time of 60 hours, the mixture is concentrated in a vacuum, the oily residue is divided between 250 cc of chloroform and 150 cc of water, and after concentrating the chloroform phase, the resulting oily crude base is reacted with gentisic acid as described in Example 10. The gentisinate of the title compound has a M.P. of 176°-179° (decomp.) after recrystallization from 150 cc of methanol and 100 cc of water.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:19]([CH3:22])([O-:21])=[O:20].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:12](/[CH:13]=[CH:22]/[N+:19]([O-:21])=[O:20])=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: C[N+](=O)[O-]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(C=O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(/C=C/[N+](=O)[O-])c1Cl
Yield: 26.2 %

Procedure:
To a solution of the compound of Example 223 (0.199 g, 0.7 mmol) in methanol (5 mL) at 0° C. was added nitromethane (0.3 mL, 5.0 mmol) and 2.5 N NaOH (2.3 mL, 5.8 mmol) portionwise over 2 h. The suspension was dissolved by addition of ice-cold water and cold 2N HCl (10 mL) was added. The precipitate was filtered and washed with water to afford the crude title compound. The crude product was purified by recrystallization from aq methanol to afford the title compound as a light yellow fluffy solid (60 mg, 26%). m.p. 104°-106° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42](Cl)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([N:17]3[CH2:18][CH2:19][N:14]([C@H:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9][C@H:10]4[C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[CH2:15][CH2:16]3)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCNCC2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN([C@H]2CCN(Cc3ccccc3)C[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Rac-cis-1-[1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine (2.00 g, 5.41 mmol) was dissolved in dichloromethane (130 mL) and 9-fluorenylmethyl-chloroformate (1.71 g, 6.49 mmol) in dichloromethane (50 mL) was added at 0° C. The reaction mixture was stirred at room temperature overnight and diluted with sat sodium bicarbonate solution (100 mL). The organic phase was separated and the aqueous layer was extracted twice with 150 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with cyclohexane/ethyl acetate 6:1 gave rac-cis-4-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.75 g, 55%) as a light yellow solid, MS: m/e=592.3 (M+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:17][C:16]3[C:18]4[C@@H:19]5[CH2:28][C@H:22]([C:23]=4[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[CH2:14]2)[CH2:21][CH2:20]5)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][C@@H:13]1[O:17][C:16]2[C:18]3[C@@H:19]4[CH2:28][C@H:22]([C:23]=3[C:24]([O:26][CH3:27])=[CH:25][C:15]=2[CH2:14]1)[CH2:21][CH2:20]4)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2c(c3c1[C@@H]1CC[C@H]3C1)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [Na+]
Product: COc1cc2c(c3c1[C@@H]1CC[C@H]3C1)O[C@@H](CN=[N+]=[N-])C2

Procedure:
Treatment of [(2R*,6R*,9S*)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan-2-yl]methyl 4-methylbenzenesulfonate (1.2 g, 2.30 mmol) with sodium azide (0.78 g, 11.99 mmol) generally according to the procedure described for Intermediate 24 gave (2R*,6R*,9S*)-2-(azidomethyl)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.10 g) generally according to the procedure described for Example 2 gave 0.45 g (53%) of (9-methoxy-4-oxatetracyclo[9.2.1.02,10.03,7]tetradeca-2,7,9-trien-5-yl)methylamine as a white solid, hydrochloride salt. mp>200° C. (dec); Anal. calcd. for C16H21NO2HCl: C, 63.94; H, 7.15; N, 4.97. Found: C, 64.68; H, 7.63; N, 4.5. Separation of the stereoisomers of (9-methoxy-4-oxatetracyclo[9.2.1.02,10.03,7]tetradeca-2,7,9-trien-5-yl)methylamine provided three compounds with >99% optical purity.
Reaction SMILES: [Mg].II.Br[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.BrCC1CCC1.C(OCC)C.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23]>C(OCC)C>[CH:6]1([CH2:5][CH:22]([OH:23])[C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C=O
Reactant: BrCC1CCC1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(O)CC1CCC1
Temperature: 0 °C

Procedure:
359 mg (14.8 mmol, 1.1 eq.) of magnesium turnings were covered with diethyl ether and etched by addition of a small piece of iodine for 3-4 min. Under argon and at RT, 5 ml of a solution of 2.0 g (13.4 mmol) of (bromomethyl)cyclobutane in 30 ml of diethyl ether were added with stirring to this mixture, the reaction was stirred for 5 min (until the reaction is initiated) and the remainder of the (bromomethyl)cyclobutane/diethyl ether solution is added dropwise over a further 10 min. The reaction mixture was stirred under reflux for 1 h, cooled under a stream of argon and, with ice-water cooling, added dropwise to a solution of 2.4 ml (12.1 mmol, 0.9 eq.) of ethyl glyoxylate (50% in toluene). The reaction mixture was stirred at RT for 1 h, carefully quenched to pH 7 with 20 ml of a potassium citrate/citric acid solution (pH 5) and then adjusted to pH 4-5 with aqueous hydrochloric acid (1N). After phase separation, the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel 50, mobile phase: cyclohexane/ethyl acetate 20%-33%). Yield: 110 mg (purity 94%, 5% of theory)
Reaction SMILES: [CH3:1][CH:2]1[NH:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:15]2[CH:2]([CH3:1])[CH2:3][C:4]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[NH:6][C:5]=3[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14]2)=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1=CNC(C)Cc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)C(C)Cc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 2-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.44 (1H, br s), 8.01 (1H, s), 7.63 (2H, m), 7.52 (1H, d), 7.39 (1H, d), 7.24 (4H, m), 5.61 (1H, br s), 4.22 (2H, m), 3.43 (1H, dd), 3.10 (1H, dd), 1.19 (3H, t), 1.06 (3H, d); MS (ES): 393 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:19]2[CH:18]=[C:17](C(OCC)=O)[O:16][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=1)=[O:2].[OH-].[Na+].C1COCC1.Cl>O>[CH:18]1[C:19]2[C:3]([CH:1]=[O:2])=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][CH:17]=1
Reactant: CCOC(=O)c1cc2c(C=O)cc3c4ccccc4ccc3c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc2c3ccccc3ccc2c2occc12
Yield: 37 %

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser, and N2 inlet line with bubbler was added ethyl 11-formyl-phenanthro[1,2-b]furan-2-carboxylate (15A, 2.5 g, 7.8 mmol), 1N NaOH solution (25 mL), THF (50 mL) and H2O (25 mL). The mixture was refluxed for 2 h until it became homogeneous. The mixture was acidified with 1N HCl and the solvent removed by rotary evaporation. The crude solid was then heated to 150° with copper powder (0.9 g) and quinoline (Aldrich, 25 mL) for 1 h. The reaction mixture was cooled and the quinoline removed under vacuum to give a crude dark green solid. After chromatography and crystallization (CH2Cl2 /hexane) 0.71 g (37% yield) of phenanthro[1,2-b]furan-11-carbaldehyde, mp 145°-150°, (C,H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: Cc1ccc(C#N)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A mixture of 4-methyl-3-trifluoromethyl-benzonitrile (370 mg, 2 mmol), N-Bromosuccinimide (356 mg, 2 mmol) and benzoyl peroxide (15 mg) in CCl4 (8 mL) was stirred at 85° C. for 16 hrs. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and DCM. DCM layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid which was purified via flash chromatography (15% EtOAc in n-heptane) to yield the title compound as a solid (460 mg, 85%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:29]([N:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[CH:14]=[CH:15][C:16]3[C:7]4[N:6]([CH2:26][CH2:27][CH3:28])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:25][C:8]=4[C:9]([NH2:24])=[N:10][C:11]=3[CH:12]=2)[CH2:23][CH2:22]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(C)=O)CC4)ccc3c21
Reaction time: 36 h
Yield: 48.8 %

Procedure:
2-(Ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.3 mmol) was slurried in dichloromethane (13 mL). Acetic anhydride (0.122 mL, 1.3 mmol) was added dropwise to the slurry and the mixture was stirred for 36 hours. Saturated aqueous sodium carbonate (5 mL) was added and the reaction was stirred for 1 hour. The layers were separated and the organic fraction was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-22% CMA in chloroform). The resulting amorphous solid was triturated with boiling acetonitrile. Filtration afforded 0.270 g of 7-[(1-acetylpiperidin-4-yl)oxy]-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 178-179.5° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17]Cl)[CH3:15])[CH2:3]1.O.C(=O)([O-])[O-].[K+].[K+].[N-:26]=[N+:27]=[N-:28].[Na+]>O1CCCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][N:26]=[N+:27]=[N-:28])[CH3:15])[CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
4.5 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-chlo roethyl)-N-methylamine were added to a mixture of 40 ml water and 20 ml tetrahydrofuran. 2 g of potassium carbonate and 1 g of sodium azide were added to the mixture. The reaction solution was then stirred at room temperature for 8 hours. The reaction solution was worked up by concentrating to about 30 ml and extracting the aqueous phase with ethyl acetate. After concentration of the ethyl acetate extract, 4.5 g of crude N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-ylo xy)ethyl]-N-(2-azidoethyl)-N-methylamine were obtained, which was used in the next step without further purification.