Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])([CH3:14])[CH3:13].[Cl:20]CCl>>[ClH:20].[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:10]([NH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:11])([CH3:14])[CH3:13]
Reactant: Cc1ccc(C)c(N=C=O)c1
Reactant: CC(C)NCCCN
Reactant: ClCCl
Product: Cc1ccc(C)c(NC(=O)NCCCNC(C)C)c1
Product: Cl
Reaction time: 1 h

Procedure:
A solution of 14.7 grams of 2,5-dimethylphenylisocyanate and 50 ml. of dichloromethane was added to a stirred, cooled solution of 35 g. N-isopropyl-1,3-diaminopropane and 400 ml. of dichloromethane. The temperature was kept between -5° and 0° C. during addition. Stirring was continued at room temperature for one hour. The solution was extracted with water, then with 200 ml. of 15% hydrochloric acid (v/v). The acid extract was made basic with saturated sodium carbonate solution and extracted with dichloromethane. The dichloromethane solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in ether and saturated with hydrogen chloride. The solid was separated and recrystallized from EtOH/Et2O to obtain N-[3-(isopropylamino)propyl]-N'-(2,5-dimethylphenyl)urea, hydrochloride, m.p. 152°-154° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[C:33]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:13])=[CH:2]1)(=[O:35])[CH3:34]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(/C=C/C(=O)N(NC(=O)c2ccccc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (27 mg, 0.07 mmol, 1.0 equivalent), K2CO3 (32.2 mg, 0.23 mmol, 3.0 equivalent), DMAP (cat, 0.12 equivalent) were introduced and dissolved in DMF, after which acetic anhydride (0.015 ml, 0.15 mmol, 2.0 equivalent) was introduced. After stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=7:3:1) and dried so that solid form of (E)-N-(3-(1-acetyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (2.6 mg, 8.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:13]1[C:12]([CH3:14])=[CH:11][C:4]([O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:3][C:2]=1[CH3:1])(=[O:18])=[O:17]
Reactant: COC(=O)COc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
Methyl (3,5-dimethylphenoxy)acetate (19.4 g, 0.10 mol) was added dropwise over ca. 30 min to rapidly stirred chlorosulfonic acid (58 g, 0.50 mol)that was cooled in a −20° C. bath. After an additional 20 min, the mixture was allowed to slowly warm to room temperature. After 2 hr, the mixture was poured slowly into 400 mL of ice/water. This suspension was extracted with 400 mL of dichloromethane, and the organic layer was washed with water and concentrated. The residue was purified by flash silica gel chromatography (hexanes→dichloromethane) to yield 7.6 g (27%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:42]1[C:46]2C=CC=CC=2N=N1.Cl.CN[O:54][CH3:55].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:21])[NH:42][CH2:46][O:54][CH3:55])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccncc2)C(=O)OC(C)(C)C)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Product: COCNC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of 3-{2-[tert-butoxycarbonyl-(4-pyridin-4-yl-butyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid (1.44 g in 25 mL N,N-dimethylformamide) at 0° C. was added 540 mg of 1-hydroxybenzotriazole (HOBt) followed by 0.44 mL 4-methylnorpholine and 365 mg N,O-dimethylhydroxylamine hydrochloride. After 15 minutes, 815 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added and the mixture allowed to warm to room temperature. After 3 days reaction time, an additional portion of 540 mg of HOBt, 0.44 mL 4-methylmorpholine, 365 mg N,O-dimethylhydroxylamine hydrochloride and 815 mg EDC were added. The reaction stopped after 4 days by concentration in vacuo and reconcentration from toluene to remove all volatiles. The residue was solvated in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 30:70; then 20:80; then 0:100) gave the title compound (1.4 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH2:31]([O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)[CH3:32]>COCCOC>[CH2:31]([O:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 21.4 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-ethoxy-phenylboronic acid (42 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (12 mg, 22%). LC-MS m/e 431.27 (M+H+)
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:3])[CH3:2].[Br:29]Br>C(O)(=O)C>[CH:26]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[C:19]([Br:29])[C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:28])[CH3:27].[CH:26]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[C:17]([Br:29])[C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:28])[CH3:27]
Reactant: BrBr
Reactant: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C)C(C)C
Solvent: CC(=O)O
Product: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4c(ccc(O)c4Br)[C@H]3CC[C@]12C)C(C)C
Product: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(Br)cc4[C@H]3CC[C@]12C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of N,N-diisopropyl estr-1,3,5(10)-triene-3-ol-17β-carboxamide (1.85 g, 4.82 mmol) in 185 ml of warm acetic acid was cooled to 20° C. and 4.48 ml (4.82 mmol) of a 1.08 M solution of bromine in acetic acid was added slowly. After stirring at ambient temperature for 5 min, the reaction mixture was poured into ice water and extracted twice with dichloromethane. The combined dichloromethane extracts were washed twice with water, dried over anhydrous MgSO4 and concentrated. Chromatography (silica gel, 2% followed by 5% ether in dichloromethane) afforded 0.39 g of N,N-diisopropyl-2-bromo-estr-1,3,5(10)-triene-3-ol-17β-carboxamide and 0.75 g of N,N-diisopropyl-4-bromo-estr-1,3,5(10)-triene-3-ol-17β-carboxamide.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]2C(N3[C@H](C=[N:17][C:6]2=[CH:5][C:4]=1O)CCC3)=O.ClC(Cl)(O[C:23](=[O:29])[O:24][C:25](Cl)(Cl)Cl)Cl.C1C[O:34]CC1>>[C:5]12[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=1)[NH:17][C:25](=[O:34])[O:24][C:23]2=[O:29]
Reactant: COc1cc2c(cc1O)N=C[C@@H]1CCCN1C2=O
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=c1[nH]c2ccccc2c(=O)o1

Procedure:
This invention provides a very short route for efficient synthesis of PBD analogues, e.g. DC-81. The synthesis starts with the reaction of a substituted 2-amino benzoic acid with triphosgene in THF under reflux to form an isatoic anhydride compound, which is subsequently coupled with a substituted or unsubstituted L-proline compound in DMSO to produce a dilactam compound, followed by reaction with MOMCl. The resulting compound is then subjected to a reduction reaction in the presence of lithium borohydride (LiBH4).
Reaction SMILES: B(OC)(OC)O[CH3:3].BrC[C:10]([O:12]C(C)(C)C)=[O:11].[CH3:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]>[Zn].O1CCCC1>[OH:23][C:18]([CH3:3])([CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:17][C:10]([OH:12])=[O:11]
Reactant: C=CCCC(C)=O
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COB(OC)OC
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCCC(C)(O)CC(=O)O
Temperature: 30 °C
Reaction time: 3 h

Procedure:
Trimethyl borate (15 mL), zinc powder (washed in advance with dilute hydrochloric acid and dried for use, 4.24 g), and tert-butyl bromoacetate (9.91 mL, 48.6 mmol) were added in this order to a tetrahydrofuran solution (15 mL) of hex-5-en-2-one (5.29 g, 53.9 mmol), and the mixture was heated to 30° C. for 30 minutes using an oil bath, then brought to room temperature, and stirred for 3 hours. The mixture was separated into organic and aqueous layers by the addition of glycerol, a saturated aqueous solution of ammonium chloride, and saturated saline, and the aqueous layer was then subjected to extraction with diethyl ether. These organic layers were combined, then washed with saturated saline, and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 2 N potassium hydroxide-methanol solution (50 mL) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure. To the residue, a 1 N aqueous sodium hydroxide solution was then added, followed by washing with diethyl ether. The aqueous layer was made acidic using concentrated hydrochloric acid under ice cooling, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (5.24 g, 75%).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.[Br:22][CH:23]1[S:31][C:30]2[C:25]([N:26](Cl)[CH:27]=[C:28]([C:32]#[N:33])[CH:29]=2)=[CH:24]1.C(OCC)C>C(OCCO)C>[Br:22][C:23]1[S:31][C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:32]#[N:33])[C:29]=2[NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[CH:24]=1
Reactant: N#CC1=CN(Cl)C2=CC(Br)SC2=C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: CCOCC
Product: N#Cc1cnc2cc(Br)sc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A mixture of 4-phenoxyaniline (430 mg, 2.32 mmol), pyridine hydrochloride (244 mg, 2.11 mmol) and 2-bromo-4-chlorothieno[3,2-b]pyridine-6-carbonitrile (578 mg, 2.11 mmol) in 10 mL of 2-ethoxyethanol is heated at 125° C. for 4 hours. The mixture is poured into diethyl ether and the solids are collected by filtration. The solids are stirred with saturated aqueous sodium bicarbonate for 1 hour. The solids are collected by filtration, washed with water and diethyl ether to give 717 mg of 2-bromo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a tan solid, mp 248–250° C.; 1H NMR (DMSO-d6) δ 7.01–7.19 (m, 5H), 7.23–7.47 (m, 4H), 7.66 (s, 1H), 8.57 (s, 1H), 9.62 (s, 1H); MS 422.1, 424.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20]Cl)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][S-:23].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][S:23][CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S-]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCl
Agent: [Na+]
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCSC
Yield: 93.5 %

Procedure:
Using the general method of Example 21 Part D, 2-butyl-1-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline-4-amine (1.44 g, 4.76 mmol) was reacted with sodium thiomethoxide (0.42 g of 95%, 5.71 mmol) to provide 1.4 g of 2-butyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder.
Reaction SMILES: C([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](N)[C:8]=2[N:7]=[CH:6]1)C(C)C.C(OCCCC[CH2:28][CH:29]([CH3:31])[CH3:30])(=O)C=C.C([NH2:36])(=O)C=C.C(OCC)(=O)C>CO>[CH2:28]([N:7]1[C:8]2[C:17](=[C:16]([NH2:36])[CH:15]=[C:14]3[C:9]=2[N:10]=[CH:11][CH:12]=[CH:13]3)[N:5]=[CH:6]1)[CH:29]([CH3:31])[CH3:30]
Reactant: C=CC(=O)OCCCCCC(C)C
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Reactant: C=CC(N)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)Cn1cnc2c(N)cc3cccnc3c21

Procedure:
Using the general method of Example 17 the formulations shown below are prepared. 1-Isobutyl-1H-imidazo[4,5-c]quinolin-4-amine or 1-(2-methylpropyl)-1Himidazo[4,5-c]quinolin-4-amine that had been ground with a mortar and pestle was used. The adhesive was the 93:7 isooctyl acrylate:acrylamide copolymer prepared in Preparative Method 1 above. The solvent was 90:10 ethyl acetate:methanol. All formulations in the following Table 8 were mixed at room temperature.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14](C([O-])=O)[CH2:13][CH2:12]2)=[CH:5][C:4]=1[F:22])#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:4]1[CH:5]=[C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:20]=[CH:21][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(OCCCC2CCN(C(=O)[O-])CC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(OCCCC2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a methylene chloride (5.5 mL) solution of 0.66 g of tert-butyl=4-[3-(4-cyano-3-fluorophenoxy)propyl]-1-piperidinecarboxylate was dropwise added 1.8 mL of trifluoroacetic acid under cooling with ice over a period of 2 minutes, which was then stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and chloroform and a 1.0 mol/L sodium hydroxide aqueous solution were added to the resultant residue. The organic layer was separated and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=4:1) to provide 0.28 μg of 2-fluoro-4-[3-(4-piperidinyl)propoxy]benzonitrile as pale yellow oily form.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH3:12])[C:8](=[O:13])[CH:7]=1)=[O:5].[CH2:15]1COC[CH2:16]1>>[CH3:12][N:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:15][CH3:16])=[CH:7][C:8]1=[O:13]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccn(C)c(=O)c1
Product: CCC(=O)c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of N-methoxy-N,1-dimethyl-2-oxo-1,2-dihydropyridine-4-carboxamide (200 mg, 1.0 eq) in 10 mL anhydrous THF was added 3 M EtBrMg (0.7 mL, 2 eq) slowly at 0° C. The reaction was stirred at rt for 1 h., quenched with sat NH4Cl (aq), and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (105 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=6.8 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.61 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.57 (s, 3H), 2.89 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=3)=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[NH:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:40])([F:1])[F:39])[CH:4]=3)=[O:11])=[CH:14][CH:15]=2)=[CH:21]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cc2c[nH]c3ncccc23)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
1-(3-Trifluoromethyl-phenyl)-3-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-urea (114, 85.0 mg, 0.150 mmol) was dissolved in tetrahydrofuran (10.0 mL) and tetra-n-butylammonium fluoride (52.2 mg, 0.200 mmol) was added. After 10 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with by silica gel chromatography to give the compound (P-0262, 23 mg, 38% over steps 6 & 7). MS (ESI) [M+H+]+=411.2
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O.N([C:30]([CH3:34])(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:30]([C:8]1[C:7]([O:6][C:2]([F:14])([F:1])[CH:3]([F:4])[F:5])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:13][Br:15])[CH3:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1c(CBr)cccc1OC(F)(F)C(F)F

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (3.80 g, 18.2 mmol) in carbon tetrachloride (50 ml) were added N-bromosuccinimide (3.54 g, 19.9 mmol) and 2,2′-azobis(isobutyronitrile) (136 mg, 0.83 mmol), and the mixture was heated under reflux for 4 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to give ethyl 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(2-fluoropyridin-4-yl)-3-oxopropionate (3.5 g, 16.6 mmol) in 1,2-dimethoxyethane (35 ml) was added sodium hydride (60% in oil, 0.66 g, 16.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) to give ethyl 3-(2-fluoropyridin-4-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (4.78 g, 69%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][CH:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]4)[N:3]1[C:4]=23.[CH:30]([C:32]1[CH:33]=[C:34]([C:42]#[N:43])[C:35]2[O:40][CH2:39][CH2:38][O:37][C:36]=2[CH:41]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+].[Cl:63]CCl.CO>>[ClH:63].[O:12]=[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2](=[O:1])[N:3]3[CH:14]([CH2:15][N:16]4[CH2:17][CH2:18][CH:19]([NH:22][CH2:30][C:32]5[CH:33]=[C:34]([C:42]#[N:43])[C:35]6[O:40][CH2:39][CH2:38][O:37][C:36]=6[CH:41]=5)[CH2:20][CH2:21]4)[CH2:13][N:5]1[C:4]=23
Reactant: ClCCl
Reactant: N#Cc1cc(C=O)cc2c1OCCO2
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N#Cc1cc(CNC2CCN(CC3Cn4c(=O)ccc5ccc(=O)n3c54)CC2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
1-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (2:1 mixture of R:S) (60 mg, 0.2 mmol) and 7-formyl-2,3-dihydro-1,4-benzodioxin-5-carbonitrile (for a synthesis see WO06014580 Preparation 13 or WO2007122258 Example 31(d)) (37.8 mg, 0.2 mmol) were dissolved in dichloromethane/methanol (2/0.1 ml) at room temperature under argon and stirred at room temperature for 1 h. This was then treated with NaBH(OAc)3 (85 mg, 0.4 mmol) and left to stir for 1 hour. A saturated solution of sodium bicarbonate (15 ml) was then added and the aqueous was extracted with 20% methanol/dichloromethane (3×35 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated. The crude was purified by silica chromatography using a 0-20% methanol/dichloromethane gradient to provide the free base of the title compound as a pale yellow gum (26 mg, 27%).
Reaction SMILES: C([C:3]1[N:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[C:9]([CH3:17])[C:8]([F:18])=[C:7](F)[C:6]=2[F:20])C.C(OC([NH:36][CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:36][CH:37]1[CH2:41][CH2:40][N:39]([C:7]2[C:6]([F:20])=[C:5]3[C:10]([C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3][N:4]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:9]([CH3:17])[C:8]=2[F:18])[CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCc1c(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c2n1-c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 0.40 g (1.00 mmol) of ethyl 6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.22 g (1.18 mmol) of 3-t-butoxycarbonylaminopyrrolidine, 0.30 g (3.00 mmol) of triethylamine, and 15 ml of acetonitrile was refluxed for 18 hours. The mixture was cooled and concentrated. The residue was dissolved in 10 ml of 6N hydrochloric acid, refluxed for three hours, and cooled to room temperature. The solids were filtered, washed with water and ether, and suspended in water. The suspension was made basic (pH 12) and filtered through a fiberglass pad, and the filtrate was neutralized to pH 6.7. The solids were filtered and washed with water and ether to give 0.38 g of the title compound, mp 230°-232° C.