Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([O:20][CH3:21])[C:5]2[O:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])([CH3:10])[CH2:7][C:6]=2[C:18]=1[CH3:19].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[OH:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([O:20][CH3:21])[C:5]2[O:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:16])([CH3:10])[CH2:7][C:6]=2[C:18]=1[CH3:19]
Reactant: C1COCCN1
Reactant: COc1c(O)c(C)c2c(c1OC)OC(C)(CCCCC(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CCCCC(=O)N1CCOCC1)C2
Yield: 85 %

Procedure:
A solution (25 ml) of 5-(2,3-dihydro-5-hydroxy-6,7-dimethoxy-2,4-dimethylbenzofuran-2-yl)valeric acid (2.0 g), morpholine (0.81 ml) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.4 g) in N,N-dimethylformamide was stirred under an atmosphere of argon at room temperature for 2 hours. The reaction mixture was made acidic by adding 1N hydrochloric acid to the mixture, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound (2.1 g, 85%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C(O)C.[Pt]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:5]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:16][CH:17]=1
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Agent: [Pt]
Solvent: CCO
Product: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Yield: 74.4 %

Procedure:
51 g of 1-methyl-4-(4-nitrophenoxy)-4-phenylpiperidine are dissolved in 1.5 liters of ethanol and are hydrogenated under a hydrogen pressure of 1 atmosphere in the presence of platinum. The catalyst is filtered off, the filtrate is concentrated to 300 ml and crystals (which have separated out) are collected. 34.3 g of the title compound of m.p. 173° to 174° C. are obtained by successive concentration of the filtrate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:10]1[CH:11]=[CH:12][CH2:13][CH:14]1[C:2]1[CH:9]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH:7]=[O:8]
Reactant: O=Cc1cccc(Br)c1
Reactant: C1=COCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cccc(C2CC=CO2)c1
Temperature: 45 °C
Yield: 38.3 %

Procedure:
Ex-119A: 5-Bromobenzaldehyde (0.5 g, 2.7 mmol) and 2,3-dihydrofuran (0.56 g, 8.1 mmol) were dissolved in dioxane (5.0 mL). Nitrogen was bubbled into the solution for 15 min followed by the sequential addition of cesium carbonate (0.96 g, 2.9 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.027 mmol). The solution was immediately heated to 45° C. and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:9) gave 0.18 g (40%) of 3-(2,3-dihydro-furan-2-yl)-benzaldehyde as a clear, colorless oil. 1H-NMR (300 MHz, CDCl3) δ 10.03 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, J=7.2 Hz), 7.62–7.64 (m, 1H), 7.53 (t, 1H, J=7.2 Hz), 6.48 (q, 1H, J=Hz), 5.60 (dd, 1H, J=8.1, 10.8 Hz), 4.98 (q, 1H, J=3.3 Hz), 3.15 (ddt, 1H, J=15.0, 8.1, 2.5 Hz), 2.59 (ddt, 1H, J=15.0, 8.1, 2.5 Hz). MS (EI) m/z=174 ([M]+, 100%). HRMS (EI) Calcd. for C11H10O2: 174.0681. Found: 174.0677.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[C:11](\[C:17]#[N:18])/C(OCC)=O)/[CH2:6][CH2:5]2.[C-:19]#[N:20].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:11][C:17]#[N:18])([C:19]#[N:20])[CH2:6][CH2:5]2
Reactant: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)ccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCc2cc(Cl)ccc21
Temperature: 65 °C
Reaction time: 21 h
Yield: 43.7 %

Procedure:
To a solution of (E)-ethyl 2-(5-chloro-2,3-dihydro-1H-inden-1-ylidene)-2-cyanoacetate (Prep5, 100 g, 0.38 mol) in ethanol (800 ml) a solution of KCN (67.5 g, 1 mol) in water (230 ml) was added and the reaction mixture was warmed to 65° C. and stirred for 21 h. Then the solvent was removed under vacuum The residue was treated with ether and the organic phase washed with water. Solvent was evaporated and the crude obtained was purified by crystallization from ethanol to obtain the title compound (36 g, y=43.5%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:31]
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(F)cc1F
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(F)cc2F)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]#[N:40]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]#[N:40])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(O)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCC#N)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenol (0.260 g, 0.668 mmol) was reacted with K2CO3 (0.111 g, 0.802 mmol) and bromoacetonitrile (0.096 g, 0.802 mmol) in acetone (5 ml) to give the product (0.271 g, 0.633 mmol, 95%) as a viscous oil. 1H NMR (DMSO-d6) δ 1.72 (s, 3H), 5.22 (s, 2H), 5.33 (s, 2H), 6.85-6.89 (m, 3H), 7.11-7.14 (m, 3H), 7.17 (t, J=7.2 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.33-7.35 (m, 3H), 7.39-7.47 (m, 5H); [ESI(+)], m/z 429 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)[CH2:37][CH3:38]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([O:39][CH2:36][CH2:37][CH3:38])[CH:45]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCCOc1cccc(B(O)O)c1
Product: CCCOc1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-propoxyphenylboronic acid (36 mg, 0.2 mmol) to give 5-{-4-[4-(2,4-dichloro-phenyl)-2-(3′-propoxy-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: FC(F)(F)C(O)=O.CC1(C)[N:13](C(O)=O)[C@@H:12](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH2:11][O:10]1.[OH-].[Na+]>O.C(#N)C>[NH2:13][C@@H:12](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:11][OH:10]
Reactant: CC1(C)OC[C@H](/C=C/c2ccc([N+](=O)[O-])cc2)N1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](/C=C/c1ccc([N+](=O)[O-])cc1)CO
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of trifluoroacetic acid (4.9 ml) in water (24 ml) was added (S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylic acid tent-butyl ester (Example 14(a)) (5.0 g) in acetonitrile (4.0 ml). After stirring at 80° C. for 4 hours, the reaction mixture was cooled to room temperature and the solution basified to pH>11 by dropwise addition of a 1N solution of sodium hydroxide The mixture was extracted three times with ethyl acetate, the combined organic layers were dried (MgSO4) and concentrated in vacuo to yield (E)-(S)-2-Amino-4-(4-nitro-phenyl)-but-3-en-1-ol as a brown oil (2.5 g). 1H-NMR (300 MHz, CDCl3, δ); 8.23-8.11 (m, 2H), 8.54-8.47 (m, 2H), 7.67 (d, J=16 Hz, 1H), 6.7 (dd, J=16 and 8 Hz, 1H). 3.78-3.69 (m, 2H), 3.58-3.42 (m, 1H).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[CH2:10]([O:17][C:18]([N:5]([CH2:6][C:7]([OH:9])=[O:8])[CH2:4][C:1]([OH:3])=[O:2])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(carboxymethyl)glycine (13.31 g, 100.00 mmol) in aqueous 2N NaOH (100 mL) was added a solution of benzylchloroformate (18.77 g, 110.00 mmol) in aqueous 2N NaOH (55 mL) at 0° C. The reaction was stirred at room temperature overnight and washed with Et2O. The aqueous layer was acidified to pH 2 with aqueous 1N HCl solution and extracted four times with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a clear oil.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)c2ccccc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
0.95 g (2.2 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) were dissolved, under nitrogen atmosphere and magnetical stirring, in 12 ml of dry CH2Cl2; 0.37 ml (2.6 mmol) of TEA were added, the solution cooled to 0° C. and 0.3 ml (2.6 mmol) of benzoyl chloride, dissolved in in 3 ml dry CH2Cl2 were added dropwise. The reaction was left 30 minutes at 0° C., then allowed to reach room temperature and left overnight. The mixture was evaporated in-vacuo to dryness, the residue was dissolved in CH2Cl2, and washed with H2O, 20% citric acid, sat. sol. NaHCO3, sat. sol. NaCl; the organic layer was dried over Na2SO4 and evaporated in-vacuo to dryness. The residue was triturated with hot i-Pr2O/i-PrOH to yield 0.8 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][OH:14].[OH-].[Na+].Cl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: OCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(OCCCO)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 4-methoxyphenol (1.24 g) and 3-bromopropanol (1.18 ml) in DMSO (15 ml) was added in one portion powdered sodium hydroxide (1.12 g). The mixture was stirred for 0.75 h then poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml). The organic phase was washed with water (100 ml), dried and concentrated to give the title compound (1.785 g) as a pale brown solid, m.p. 56°-60°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]([N:13](C(C)C)C(C)C)C.O>ClCCl.O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CN1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
Bromonitrile (11.12 g) is added to a mixture of 1,4-dioxa-8-aza-spiro[4.5]decane (10.00 g) and ethyldiisopropylamine (59.92 mL) in dichloromethane (125 mL) and tetrahydrofuran (125 mL). The reaction mixture is stirred over night at room temperature. Water is added and the organic phase is separated, dried over Na2SO4 and concentrated in vacuo to give the title compound. TLC: rf=0.80 (aluminum oxide, ethyl acetate/petrol ether 3:1); Mass spectrum (ESI+): m/z=169 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([NH:5][CH2:6][C:7]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[O:43]1CCOC[CH2:44]1>>[CH3:4][C@H:3]1[C@@H:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:1][C:44](=[O:43])[N:5]1[CH2:6][C:7]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H](NCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1)[C@H](O)c1ccccc1
Reactant: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(3-{2-[((1S,2R)-2-Hydroxy-1-methyl-2-phenyl-ethylamino)-methyl]-4-trifluoromethyl-phenoxy}-phenyl)-acetic acid (0.15 g, 0.33 mmol), N,N′-carbonyldiimidazole (0.065 g, 0.4 mmol), and diisopropylethylamine (1 mL) were combined in 1,4-dioxane (5 mL) and stirred at 80° C. overnight. After work-up, the crude material was purified by preparative HPLC to give the desired product (0.04 g).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)(=[O:4])[CH2:2][CH3:3].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.Cl.[CH2:33](O)CC>>[CH3:13][N:9]1[C:8]2[CH:14]=[CH:15][C:5]([C:1](=[O:4])[CH:2]([CH3:33])[CH2:3][N:27]3[CH2:28][CH2:29][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=4)[CH2:25][CH2:26]3)=[CH:6][C:7]=2[O:11][C:10]1=[O:12]
Reactant: CCC(=O)c1ccc2c(c1)oc(=O)n2C
Reactant: CCCO
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Product: CC(CN1CCN(c2cccc(C(F)(F)F)c2)CC1)C(=O)c1ccc2c(c1)oc(=O)n2C

Procedure:
0.025 mole of 6-propionyl-3-methylbenzoxazolinone, described in French Patent No. 73/23,280, and 0.038 mole of 1-(3-trifluoromethylphenyl)piperazine are dissolved in 150 cm3 of propanol in a 250-cm3 groundnecked flask equipped with a reflux condenser and a magnetic stirrer. 0.038 mole of trioxymethylene and 1.5 cm3 of concentrated hydrochloric acid are added. The mixture is heated to reflux for 72 hours. The precipitate formed is drained, washed with acetone, suspended in water and alkalinized with sodium hydroxide. The mixture is extracted several times with chloroform, the organic phases are combined, dried over calcium chloride, filtered and evaporated on a water bath under vacuum and the residue is recrystallized in propanol.
Reaction SMILES: [F:1]C1C(F)=C(F)C(F)=C(F)C=1F.C(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]2[N:24]=[C:25]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:26]([C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[C:19]2[CH:18]=1>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CC(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([F:1])[N:20]2[N:24]=[C:25]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:26]([C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:28])=[C:19]2[CH:18]=1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cc(Cl)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [C-]#N
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(F)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing tetrabutylammoniumcyanide and THF (0.912 mL, 1.0 M) was added a solution containing hexafluorobenzene and THF (0.760 mL, 0.2 M) at −35° C. (caution, exothermic). The solution was removed from cooling and maintained at ambient temperature for 150 min. The solution thus obtained was cooled to 0° C. (ice bath) and added dropwise with stirring to a pre-cooled solution (−50° C., dry ice, acetone) containing tert-butyl 5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate and THF (0.608 mL, 0.38 M). The solution thus obtained was removed from cooling and allowed to proceed for 18 h. The solution was poured into water (25 mL). The aqueous portion was then extracted with ethyl acetate (2×25 mL). The organic portions were combined, then washed with water (3×20 mL), then washed with brine (25 mL), then dried over MgSO4, filtered and concentrated. The residue thus obtained was purified on silica gel (0-20% ethyl acetate/hexanes, 25 min gradient) to afford tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65-7.76 (m, 3H), 7.11-7.20 (m, 2H), 6.64 (dd, J=4.77, 2.01 Hz, 1H), 3.27 (s, 3H), 1.12 (s, 9H). LCMS retention time: 2.743 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 422 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)(=[O:38])[CH3:37].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:36](=[O:38])[CH3:37])[C:15]1[C:16]([O:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[N:17][C:18]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2nc(-c3cncnc3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Oc2nc(-c3cncnc3)ncc2N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Compound 8b (89 mg; 0.19 mmol) in CH2Cl2 (7 mL) was added acetyl chloride (0.1 mL) and pyridine (0.1 mL) at ambient temperature. The mixture was stirred at room temperature for 3 h. Diluted the resulted mixture with CH2Cl2. The organic phase was washed sequentially with H2O and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to afford Compound 9a. The crude product was used in the next reaction without further purification. MS: m/z 521.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][C:1]([C:20]3[CH:19]=[CH:15][C:14]([OH:13])=[CH:22][C:21]=3[OH:23])=[N:5][C:4]=2[CH:6]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: Oc1ccc(-c2nc3cc(O)ccc3o2)c(O)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 2,4-dimethoxybenzoic acid and was obtained as a white solid, m.p. greater than 300° C.; MS m/e 242 (M−H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([CH2:34][CH2:35][O:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:45]C1C=CC2C3N(CC(C)C)C(C)=NC=3C=NC=2C=1)C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[C:20]([CH2:34][CH2:35][O:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N+:16]([O-:45])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Product: COCCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 28 h

Procedure:
A modification of the general method described in Part B of Example 3 was followed using tert-butyl {4-[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (9.08 g, 17.9 mmol) in lieu of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline. Over a period of 28 hours, three equivalents of mCPBA were added. Following the work-up procedure, 8.07 g of tert-butyl {4-[7-benzyloxy-2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate were obtained.
Reaction SMILES: [I-].[O:2]1[C:6]2([CH2:11][CH2:10][C:9]([C:12]3[CH:17]=[CH:16][N+:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[OH-:19].[Na+]>C1COCC1>[O:2]1[C:6]2([CH2:11][CH2:10][C:9]([C:12]3[CH:13]=[CH:14][N:15]([CH3:18])[C:16](=[O:19])[CH:17]=3)=[CH:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: C[n+]1ccc(C2=CCC3(CC2)OCCO3)cc1
Reactant: [OH-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc(C2=CCC3(CC2)OCCO3)cc1=O

Procedure:
4-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-1-methyl-pyridinium iodide (as prepared in the previous step, 864 mg, 2.40 mmol) in THF (5 mL) and 1N NaOH (5 mL) was treated with K3Fe(CN)6 (Aldrich, 1.58 g, 4.80 mmol) at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.