Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[C:11]1([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([N:22]1[CH2:23][CH2:24][CH:19]([C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])[CH2:20][CH2:21]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
Neat DIPEA (1.54 ml, 8.86 mmol) was added dropwise to a solution of phenyl(4-piperidinyl)methanone hydrochloride (1 g, 4.43 mmol) in CH2Cl2 (20 ml) at 0° C. Then, neat MsCl (377 μL, 4.87 mmol) was slowly added and the cooling bath was removed. After 30 minutes, the reaction was quenched with water and diluted with CH2Cl2. After separation, the organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The final ketone 1 was obtained as a white solid (1.16 g, 98%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH3:23].[CH2:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:25]>ClCCCl.ClCCl>[Br:11][C:12]1[C:13]([O:22][CH3:23])=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=2)[CH:17]=1
Reactant: COc1cc(NC(C)=O)ccc1Br
Reactant: CCc1ccc(C(=O)O)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2NC(C)=O)cc1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (17 mL) and tin(IV) chloride (5 mL) are successively added to a suspension of N-(4-bromo-3-methoxy-phenyl)-acetamide (5.0 g) and 4-ethylbenzoic acid (4.4 g) in 1,2-dichloroethane at such a rate that the temperature maintains below 35° C. The resulting mixture is heated at reflux temperature overnight. Then, the mixture is diluted with dichloromethane and poured onto crushed ice. After stirring the aqueous mixture for 30 min, the organic phase is separated and washed with 10% NaOH in water and water. The organic phase is dried (sodium sulphate), the solvent is removed and the residue is triturated with methanol to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1.C([Li])CCC.[I:27]I>O1CCCC1.CCCCCC>[I:27][C:10]1[N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[C:5]2[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=2[CH:11]=1
Reactant: II
Reactant: COc1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ncnc2c1cc(I)n2S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 4-methoxy-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [2.23 g, Reference Example 7] in tetrahydrofuran (35 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (5 mL, 1.6M) under inert atmosphere. The solution was stirred at −70° C. for 1 hour and iodine (2.05 g) was added. The reaction mixture was stirred at −70° C. for another 1 hour, allowed to reach room temperature and partitioned between ethyl acetate and aqueous sodium sulfite solution. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure to give the title compound (2.64 g) as an amorphous solid. MS: 430 [MH]+. LCMS (Method B) RT=4.15 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([NH2:41])=[O:40]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:38][C:39]([NH2:41])=[O:40])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 4.8 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in THF (I ml) and DMF (5 drops) on ice was added sodium hydride (0.024 g, 0.6 mmol). To the flask was added bromoacetamide (0.083 g, 0.6 mmol). While warming to room temperature the reaction was allowed to stir for 6 hours. The reaction was quenched with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. The product was purified by HPLC as described above to yield the title compound (0.005 g, 4.8% yield): ES-MS (m/z) 518 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:16])[C:9]2[CH:15]=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH:3]([CH3:5])[CH3:4].[BH-](O[C:34]([CH3:36])=[O:35])(OC(C)=O)OC(C)=O.[Na+].[C:38]([O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH:47]=O)([CH3:41])([CH3:40])[CH3:39]>ClCCl>[NH2:44][CH2:45][CH2:46][CH2:47][N:1]([C@@H:2]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:16])[C:9]2[CH:15]=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH:3]([CH3:5])[CH3:4])[C:34](=[O:35])[C:36]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1.[C:38]([O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH2:47][NH:1][CH:2]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:16])[C:9]2[CH:15]=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH:3]([CH3:5])[CH3:4])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)C(N)c1nc2ccncc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2ccncc2c(=O)n1Cc1ccccc1
Product: Cc1ccc(C(=O)N(CCCN)[C@@H](c2nc3ccncc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 285.3 %

Procedure:
To a solution of dichloromethane (100 mL), 2-(1-amino-2-methyl-propyl)-3-benzyl-3H-pyrido[4,3-d]pyrimidin-4-one (1.92 mmol) and Na(OAc)3BH (0.814 g, 3.84 mmol), was added t-butyl-N-(3-oxopropyl)-carbamate (0.400 g, 2.30 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours, after which it was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. After concentration under reduced pressure, the desired product {3-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[4,3-d]pyrimidin-2-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (0.850 g, 95%) was obtained in sufficiently pure form to be carried forward for use in the next step. MS (Cl) M/E: 466.2.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:11])=[O:10])=[CH:5][CH:4]=1.Br.[OH2:13]>CS(C)=O>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:10])[CH:11]=[O:13])=[CH:5][CH:4]=1)[CH3:1]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: O
Agent: Br
Solvent: CS(C)=O
Product: CCc1ccc(C(=O)C=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
4-Ethylacetophenone (26.72 mmol, 4 mL) was dissolved in dimethyl sulfoxide (27 mL), and 48% hydrobromic acid (11 mL) was gradually added at room temperature. After overnight stirring at 70° C., the reactor was cooled to room temperature. The reaction solution was poured into water (50 mL) and stirred for about 1 hour. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a white solid (2.44 g, yield 56%).
Reaction SMILES: Cl.Br[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH2:11](N(CC)CC)C.[N:18]1[C:27]2[C:22](=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28]([OH:30])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCOC(C)=O.CN(C=O)C>[CH3:11][C:9]1[CH:10]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH:8][C:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[N:24][CH:23]=2)[N:18]=1)=[O:30]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: NCc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 4-bromobenzylamine hydrochloride (97.8 mg, 98%, 0.43] mmol) in anhy. DMF (5 ml) was added triethylamine (60.1 ul. 0.431 mmol), After 5 min, 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol) was sequentially added. The resulting mixture was allowed to stir at room temperature for overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aq. NaHCO3, dried over anhy. MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc =1:1 to pure EtOAc) afforded desired product as white solid (97 mg, 99 m.p. 149-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(C(C)C)CC)(C)C.Cl.[NH2:20][OH:21]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([NH:20][OH:21])=[NH:6]
Reactant: N#Cc1cccc(F)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1cccc(F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
3-Fluorobenzonitrile (2.5 g, 0.021 mol), diisopropylethyl amine (10.8 mL, 0.062 mol) and hydroxylamine hydrochloride (4.3 g, 0.062 mol) were mixed in ethanol (30 mL). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated to half the original volume. The residue was added to a mixture of dichloromethane (200 mL) and water (60 mL). The mixture was basified to pH 9 using 2N NaOH and the organic phase was separated. The aqueous phase was extracted further with dichloromethane (2×50 mL) and the combined organic phase was washed with water (75 mL), washed with brine (75 mL), dried over sodium sulfate and concentrated to give the product as a yellow solid (2.8 g, 89%). 1H NMR (300 MHz, CDCl3): δ 8.05 (bs, 1H), 7.39 (m, 3H), 7.16 (m, 1H), 4.88 (bs, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-])=O.P(Cl)(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:24]>C(O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2[O:7][N:1]=[C:4]3[C:5]=2[CH:8]=[C:9]([Cl:24])[CH:10]=[CH:11]3)=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Reactant: Cl
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ccc(-c2onc3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a mixture of 100 g (0.662 mole) of o-nitrobenzaldehyde and 160 g (1.05 mole) of phosphorus oxychloride was added dropwise with stirring 100 g (1.08 mole) of aniline, keeping the temperature below 30°. After 3 hr. at room temperature it was heated to 75° for 18 hr. and at 90° for 3 hr. (The reaction becomes exothermic when heated). The mixture was cooled, 200ml of ethanol and 200 ml of concentrated hydrochloric acid were added, then heated to reflux for 3 hr. with stirring. On cooling, the precipitate formed was collected and washed with acetone, then resuspended in dilute ammonium hydroxide for 1 hr. and collected again. After crystallization from ethanol, 70 g (86%) of product was obtained. Recrystallization from ethanol gave orange rods, mp 208°-211°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]([CH2:12][C:13](O)=O)[C:9](O)=O)[CH:7]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[CH2:18]([N:25]1[CH2:13][CH2:12][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(Cl)cc1C(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(Cl)cc1C1CCN(Cc2ccccc2)C1

Procedure:
1.0 g of 2-(5-chloro-2-methoxyphenyl)succinic acid is suspended in 50 ml of xylene, 0.47 ml of benzylamine is added and the mixture refluxed for 8 hours with separation of water. The solvent is evaporated and the residue taken up in ethylacetate and extracted with 2N HCl, followed by 2N NaOH and aqueous NaCl. The organic layer is dried, filtered and the solvent evaporated. The dried residue is purified by flash chromatography using t-butylmethylether/hexane 1/1 providing the amorphous product: MS (EI): M+=329; NMR (DMSO): 2.65 (1H, dd), 3.1 (1H, dd), 3.45 (3H, s), 4.2 (1H, dd), 4.6 (2H, s), 7.0 (1H, d), 7.25-7.4 (7H, m).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:9]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCC(=O)C1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(OCc2ccccc2)CCC1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer and Dean-Stark apparatus was added 1,3-cyclohexanedione (60.0 g, 535 mmol), toluene (450 ml), p-toluenesulfonic acid monohydrate (1.35 g, 5.20 mmol) and benzyl alcohol (52.6 g, 487 mmol). The resulting solution was heated to reflux temperature for 12 hr. The reaction mixture was cooled to room temperature and then washed with saturated aqueous sodium carbonate solution (2×100 ml). The organic layer was then washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a brown oil (94.9 g) which crystallised upon standing for 17 hr. The crude crystalline material was slurried in isopropyl ether (20 ml). The mixture was filtered and the crystalline material was washed with ice cold isopropyl ether (3×30 ml), then with cold petroleum ether (2×20 ml). The resulting peach coloured crystalline solid was dried overnight under reduced pressure, furnishing the desired product (74.4 g, 76%). m/z (ES+) 203 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[C:10]([CH2:18][CH3:19])([CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH2:18][CH3:19])[CH3:17]
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1N(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1N(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.7 g) and 1-benzyl-4-dimethylamino-3-ethyl-3-methyl piperidine (6 g, 23 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at room temperature. The catalyst was filtered off, washed with methanol and filtrate was concentrated to afford 4-dimethylamino-3-ethyl-3-methylpiperidine. Yield 2.8 (72%), C10H22N2, m/z 171 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3Cl)[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3[N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[CH2:21][CH2:20]2)=[O:18])=[C:9]1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1c(C(=O)N2CCC(n3c(Cl)nc4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Product: Cc1c(C(=O)N2CCC(n3c(N4CCN(C)CC4)nc4ccccc43)CC2)c2ccccc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 22 %

Procedure:
A mixture of 20 mg (0.041 mmol) of (1-benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (the preparation of which is described in example 1) and N-methyl-piperazine was heated in a sealed tube at 90° C. for 8 hours, cooled to RT and then concentrated in vacuo. Flash chromatography (CH2Cl2/MeOH 9/1) afforded 5 mg (22%) of (1-benzyl-2-methyl-1H-indol-3-yl)-{4-[2-(4-methyl-piperazin-1-yl)-benzoimidazol-1-yl]-piperidin-1-yl}-methanone as white solid. ES-MS m/e (%): 547.5 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].C(O)=O.C(NC[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)C.CO>O1CCCC1>[CH:1]([N:8]([CH2:9][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH2:12][CH3:11])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNCCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O=CO
Product: CCN(C=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (326 mmole, 52.81 g) in tetrahydrofuran (164 ml) cooled to 0° C., was added dropwise 96% formic acid (326 mmole, 14.99 g) over a 26 minute period. Reaction stirred at 0° C. for 30 minutes then a light suspension of N-ethyl-p-hydroxyphenethylamine (102 mmole, 16.88 g) in tetrahydrofuran (66 ml) was added over a 10 minute period. Reaction then stirred at 22° C. for 170 minutes before being treated with methanol (10 ml). After stirring for 90 minutes, reaction was concentrated in vacuo to an oil containing crystals. The mixture was taken up into methylene chloride and subjected to preparatory chromatography eluting with a gradient of 0 to 5% methanol:methylene chloride over a thirty-minute period. The fractions containing the title compound were combined, concentrated in vacuo to afford 13.46 g of an oil that slowly crystallizes out. Fractions containing title compound and impurities were resubjected to preparatory column chromatography under the same conditions described above to afford an additional 2.61 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:39]=[CH:38][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:34][CH3:35])=[C:21]([NH:24][C:25](=[O:32])[CH:26]=[CH:27][CH2:28][CH2:29][CH2:30]Cl)[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:36]#[N:37])=[CH:11][C:10]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].C[N:44]([CH3:47])[CH:45]=O.[CH3:48][NH:49][CH3:50]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:39]=[CH:38][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:34][CH3:35])=[C:21]([NH:24][C:25](=[O:32])[CH2:26][CH:27]([N:49]([CH3:50])[CH3:48])[CH2:28][CH2:29][CH2:30][N:44]([CH3:47])[CH3:45])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:36]#[N:37])=[CH:11][C:10]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)C=CCCCCl
Reactant: CNC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)CC(CCCN(C)C)N(C)C
Temperature: 50 °C

Procedure:
A stirred mixture of N-{4-[4-(Benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}6-chloro-2-hexenamide (0.58 g, 1.0 mmol), NaI (0.15 g, 1.0 mmol), tetrabutylammonium iodide (74 mg, 0.20 mmol), 4.0 ml of dimethylformamide, and 10 ml of 2.0 M dimethylamine in tetrahydrofuran was heated at 50° C. for 8 h. After the addition of 5 ml more 2.0 M dimethylamine in tetrahydrofuran the mixture was heated at 50° C. for an additional 8 h. After evaporation of the dimethylamine and tetrahydrofuran, the mixture was stirred in water, brought to pH˜9 with potassium carbonate, and filtered. The crude product was washed with water, dried, and chromatographed on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give 464 mg of the title compound as an off-white solid; mass spectrum (electrospray, m/e) 628.9 (M+H)+, 315.1 (M+2H)+2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(F)c(Cl)c1
Reaction time: 8 h
Yield: 29 %

Procedure:
3-Chloro-4-fluorobenzoyl chloride (60 mg, 0.31 mmol, CAS RN 65055-17-6) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the product as a waxy solid (23 mg, 29%). MS (ESI): m/z=355.0 [M+H]+.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH3:6])=[O:4])=[O:2].[O:8]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:8]([CH2:15][C:16]1[O:21][CH2:20][CH2:19][CH2:18][C:17]=1[C:1](=[O:2])[C:3]([O:5][CH3:6])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(=O)Cl
Reactant: C1=C(COc2ccccc2)OCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)C1=C(COc2ccccc2)OCCC1
Reaction time: 8 h
Yield: 36.2 %

Procedure:
35 g (0.29 mol) of methoxalyl chloride are added dropwise to 31 g (0.16 mol) of 6-phenoxymethyl-2,3dihydropyran (Example 7c), 39.5 g (0.5 mol) of pyridine and 2.5 g (0.02 mol) of p-dimethylaminopyridine in 200 ml of methylene chloride. During this procedure, the reaction mixture warms up to 30°-35 ° C. Stirring is carried out overnight and the reaction mixture is then poured onto water. The aqueous phase is separated off and the organic phase is extracted once again with water. The organic phase is then dried over MgSO4 and evaporated down. The residue is purified by column chromatography using hexane/ethyl acetate mixtures. 16 g of starting material and 8.5 g (0.031 mol=19%, pale yellow oil) of the title compound are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCCOCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCN(CCOCCO)CC2)cc1
Temperature: 120 °C
Yield: 67.6 %

Procedure:
A mixture of 54.3 grams (0.61 mol) of N-[2'-(2"-hydroxyethoxy)ethyl]piperazine, 50 grams (0.40 mol) of 4-fluorobenzaldehyde, 50 grams of anhydrous potassium carbonate, and 50 mL of DMSO was heated to 120° C. for four days under nitrogen. After cooling to room temperature, the solution was diluted with one liter of water. The aqueous solution was "processed" as follows. It was extracted with dichloromethane; the separated organic layers were combined and dried over anhydrous magnesium sulfate or sodium sulfate. The organic layer was separated, and solvent was removed on a rotary evaporator under reduced pressure (hereafter these steps will be referred to as "processed" and the product was dried under vacuum overnight to afford 75.3 grams (96%) of 4-[4'-(2"-(2'"-hydroxyethoxy)ethyl)piperazino]benzaldehyde (F).