Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[Na+]>CS(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:49]#[N:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC#N)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 50 °C

Procedure:
To a stirred solution of 0.90 g of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 18b) in 10 ml of dimethylsulfoxide are added 0.25 g of sodium cyanide and the mixture is heated to 50° C. for 4 hours. The reaction mixture is diluted with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.30 (EtOAc-heptane 1:1); Rt=5.20.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>O1CCCC1>[Cl:34][CH2:35][CH2:36][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:38]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
2 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)-ethyl]piperazine and 0.82 g of Hunig base are introduced into 40 ml of tetrahydrofuran, and a solution of 0.8 g of 3-chloropropionic acid chloride is added dropwise thereto. The solution is left to stand overnight. The resulting suspension is concentrated by evaporation and taken up in methylene chloride and water. There is obtained from the organic phase 1-[4-(3-chloropropionylamino)benzoyl]-4-[2-(4-chlorophenyl)-ethyl]piperazine having a melting point of 190°-191°.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:18])[C:6]1[CH:15]=[CH:14][CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[C:7]=1[O:16][CH3:17].[CH3:19]O>>[CH3:19][C:14]1[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([O:16][CH3:17])=[C:6]([CH:15]=1)[C:5]([OH:4])=[O:18]
Reactant: COC(=O)c1cccc(C(=O)OC)c1OC
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)cc(C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
An aqueous solution of sodium hydroxide (5M, 100 mL) was added under cooling to a solution of 5 (0.5 mol) in methanol (1.5 L). The mixture was stirred for 3 days at room temperature. The solvents were removed under reduced pressure and the residue dissolved in hot acetone (2 L). A thick paste precipitated from the acetone solution overnight (room temperature). TLC reveals that the upper acetone solution mainly contained the starting diester and the mono-sodium salt of the acid and that the lower paste was a mixture of the mono- and disodium salt of the acid. Acetone was removed from both fractions and the chromatographic separation on a gradient flash silica gel column (0-3% methanol in CH2Cl2) of both fractions gave 40 g the desired product. Yield 63%. 1H NMR (500 MHz, CDCl3, 25° C.), δ: 3.913 (s, 3H, OCH3), 3.982 (s, 3H OCH3), 7.252 (t, J=7.75, 1H, ArH), 7.991 (d, J=7.5, 1H, ArH), 8.166 (d, J=7.5, 1H, ArH). 13C NMR (500 MHz, CDCl3, 25° C.), δ: 52.48, 64.09, 124.10, 125.67, 136.38, 136.49, 159.76, 165.46, 167.69.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([S:35]([CH3:38])(=[O:37])=[O:36])[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[I:39]N1C(=O)CCC1=O>CC(C)=O>[I:39][C:26]1[C:20]2[C:21](=[N:22][CH:23]=[C:18]([C:17]3[C:12]([NH:11][C@H:7]4[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]4)=[N:13][C:14]([S:35]([CH3:38])(=[O:36])=[O:37])=[N:15][CH:16]=3)[N:19]=2)[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[CH:25]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cc(I)c2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1 (70 mg, 0.12 mmol) in acetone (0.5 ml) was treated with N-Iodosuccinimide (41 mg, 0.18 mmol) and stirred at 20° C. for 16 hours. The crude reaction mixture was concentrated in vacuo and was purified by silica gel chromatography (0% to 40% ethyl acetate/dichloromethane) to give 67 mg (79%) of {5-[7-Iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-2-methanesulfonyl-pyrimidin-4-yl}-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 708.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: ClCCl
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask fitted with a condensor and addition funnel, N-methylpiperazine (10.0 grams, 0.1 mol) was stirred while 2-fluoronitrobenzene (14.1 grams, 0.1 mol) was added dropwise under nitrogen. Caution—a vigorous exotherm occurred when approximately 20% of the 2-fluoronitrobenzene had been added. Following completion of the addition (˜30 min.) the reaction was stirred another 60 min. at room temperature, diluted with methylene chloride (100 mL) and washed with saturated aqueous Na2CO3 and saturated aqueous sodium chloride. After drying with MgSO4, the solvent was removed in vacuo to give 2-(4-methylpiperazin-1-yl)-1-nitrobenzene as an orange oil, 20.4 grams. Mass spectrum: 221 (M+). 174 (M-HNO2) 1H-NMR (CDCl3, 300 MHz) δ 7.8-7.0 (4H, m), 3.05 (4H, m), 2.55 (4H, t), 2.3 (3H, s).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:13])[CH2:11][CH3:12]>>[CH2:10]([NH:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:11][CH3:12]
Reactant: CCCN
Reactant: N#Cc1ccccc1F
Product: CCCNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and n-propylamine.
Reaction SMILES: C(S)C.[H-].[Li+].[C:6]1([CH2:12][CH2:13][CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([O:23]C)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>CN(C)C=O>[OH:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH:14]([CH2:13][CH2:12][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:18][C:17]=2[CH:19]=1
Reactant: COc1ccc2c(c1)CC(CCc1ccccc1)O2
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CCS
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)CC(CCc1ccccc1)O2
Yield: 98 %

Procedure:
Ethanethiol (62 gm; 1 mole) was added dropwise to lithium hydride (8 gm; 1 mole) in dimethylformamide (700 mL) under nitrogen atmosphere. 2-(2-phenylethyl)-5-methoxy-2,3-dihydrobenzofuran, E4, (126 gm; 500 mmoles) in dimethylformamide (200 mL) was then added in one portion and the mixture brought to reflux for 3 hours. The mixture was poured into 1N hydrochloric acid and extracted with diethyl ether. The ether layer was separated and backwashed with water twice, dried over MgSO4, filtered and concentrated in vacuo to obtain 123 gm (98%) of 5-hydroxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E5, m.p. 56°-58° C.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13](=[O:26])[CH2:14][C@H:15]3[C@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][N:16]3C(OC)=O)[CH:6]=[N:5][C:4]=2[C:3]=1[Cl:27].[BrH:28]>C(O)C>[BrH:28].[BrH:28].[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13](=[O:26])[CH2:14][C@H:15]3[C@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][NH:16]3)[CH:6]=[N:5][C:4]=2[C:3]=1[Cl:27]
Reactant: COC(=O)N1CCC[C@@H](O)[C@@H]1CC(=O)Cn1cnc2c(Cl)c(Cl)sc2c1=O
Agent: Br
Solvent: CCO
Product: O=C(C[C@@H]1NCCC[C@H]1O)Cn1cnc2c(Cl)c(Cl)sc2c1=O
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
In a 15 ml single-neck round bottom flask equipped with a reflux condenser, a solution of 0.190 g (0.00044 mole) of methyl trans-2-[3-(6,7-dichloro-3,4-dihydro-4-oxothieno[3,2-d]pyrimidin-3-yl)-2-oxopropyl]-3-hydroxy-1-piperidinecarboxylate and 6.2 ml of 48% aqueous hydrobromic acid was immersed in an oil bath preheated to 150° C. Heating was continued for three minutes. The solution was allowed to cool to room temperature, and the volatile components were evaporated under reduced pressure. Ethanol (5 ml) was added to the residue, and again the mixture was evaporated to dryness. This operation was repeated once more to afford a dark residue which was then taken up in 3 ml of ethanol. After standing overnight at room temperature, the solution was diluted with 1 ml of ethanol and then heated at reflux briefly. Upon cooling a greyish solid precipitated. The mother liquor was removed by means of a pipette, and the residue was dried in a vacuum oven at 55° C. for 45 minutes to furnish the title compound: yield 0.080 g (48%); mass spectrum peaks at 357 (molecular ion - 18), 155, 137 (parent peak) amongst others; 1H-nmr (CF3CO2H) delta 1.3-2.0 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.8-3.4 (multiplet, 6H, COCH2CH, NCH2, NCHCH2, CHOH), 3.7 (singlet, 1H, OH), 4.9 (singlet 2H, NCH2CO), 8.3 (broad singlet, 1H, N=CH--N).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1cc(Br)ccn1)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
1.0 g (5.8 mmol) of 4-bromo-2-methylpyridine and 2.14 g (11.6 mmol) of ethyl 4-chlorobenzoate are placed under a stream of argon in a round-bottomed flask and dissolved in 10 ml of anhydrous tetrahydrofuran. The solution is cooled to 0° C. and 12 ml of a lithium hexamethyldisilazane (LiHMDS) solution (1M in tetrahydrofuran) are added. After addition, the mixture is heated at 45° C. for 3 h and cooled to ambient temperature, and then water is added. The tetrahydrofuran is subsequently evaporated under reduced pressure and the aqueous phase is extracted three times with ether. The organic phase is separated, dried and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, elution being carried out with a mixture of dichloromethane and heptane. 1.11 g (62%) of compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)CC1
Yield: 93.8 %

Procedure:
A solution of 4,4-dimethyl-cyclohex-2-enone (3 mmol) in ethyl acetate is hydrogenated overnight at room temperature using Pd/C (0.05 mmol) with hydrogen under normal pressure. Filtration over celite and then concentration by evaporation produces 4,4-dimethyl-cyclohexanone (355 mg) in a yield of 94% (J. Org. Chem. 2001, 66 (3), 733-738).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH3:15])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CC)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of 75A (228 mg, 0.85 mmol) in 3 mL THF, was added aq. LiOH (1M, 2 mL, 2 mmol), and the reaction was stirred at rt for 16 h. Water (20 mL) was added, then the mixture was acidified with 1N HCl (pH=2) and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated to afford 75B (150 mg, 73%). MS (ESI) m/z 243.0 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=O)C.[OH-].[Na+].[ClH:34]>C(Cl)Cl.CO.CO>[ClH:34].[OH:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccsc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 66 %

Procedure:
To a solution of 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline (200 mg, 0.45 mmol) in methylene chloride/methanol (1/1) (20 ml) was added, a 2M aqueous sodium hydroxide solution (0.67 ml , 1.35 mmol). The mixture was stirred for 35 minutes at ambient temperature, the solvents were evaporated, water was added to the residue and the solution was extracted with ethyl acetate. The organic layer was washed with water, brine, then dried (MgSO4) and evaporated to give a white solid. This solid was then dissolved into a saturated solution of hydrochloric acid in methanol (10 ml) and stirred for 10 minutes. The solid product was filtered and dried under a vacuum, to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline hydrochloride (127 mg, 66%). m.p. 246-248° C. 1H NMR Spectrum: (DMSOd6) 2.15(s, 3H); 3.98(s, 3H); 5.32(s, 2H); 6.98(dd, 1H); 7.10(s, 1H); 7.14(d, 1H); 7.25(d, 1H); 7.40(s, 1H); 7.61(dd, 1H); 7.70(d, 1H); 8.12(s, 1H); 8.74(s, 1 H); 9.60(s, 1H) MS−ESI: 394 [MH]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[N:5]=[C:4]([NH2:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:3]1[C:4]([NH2:11])=[N:5][C:6]([S:8][CH3:10])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)c1nc(N)cc(Cl)n1
Solvent: ClCCl
Product: CSc1nc(N)c(Br)c(Cl)n1
Reaction time: 1 h

Procedure:
To a cold stirring solution of 10 g (52.2 mmol) 6-chloro-2-(methylsulfinyl)pyrimidine-4-amine in 450 ml of DCM, 10 g (56.2 mmol) of N-bromosuccinimide were added, and stirring was continued for 1 hour at room temperature to provide 5-bromo-6-chloro-2-(methylthio)pyrimidine-4-amine, which was used without further purification in the next step (see intermediate 3). The end of the reaction is followed by thin layer chromatography.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:22])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24].[H-].[Na+].O>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:22][CH2:24][CH2:23][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A heterogeneous mixture of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanol (0.76 g, 2.6 mmol) and methyl vinyl sulfone (0.54 g, 5.11 mmol) in DMF (10 mL) was heated until a solution formed. Sodium hydride (60% dispersion in oil, 10 mg, 0.26 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) and a small amount of brine were added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 0.75 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclopropyl}methyl)-1H-imidazo[4,5-c]quinoline as a tan oil.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(O)CCCCCCCCCCc1ccc(Cl)cc1

Procedure:
By the similar procedure of synthesis of B10, compound B2 (2.20 g, 4.28 mmol) and 4-chlorobenzaldehyde (401 mg, 2.85 mmole) were used as starting materials to afford B17 (526 mg, 1.77 mmol, 62%). mp: 93° C. 1H-NMR (CDCl3, 400 MHz) δ 7.21 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 2.54 (t, J=7.5 Hz, 2H), 2.33 (t, J=7.5 Hz, 2H), 1.53-1.63 (m, 4H), 1.26 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 179.90, 141.28, 131.21, 129.71, 128.27, 35.26, 34.00, 31.35, 29.69, 29.44, 29.39, 29.36, 29.19, 29.13, 29.01, 24.64. HRMS (ESI) calculated for C17H25ClO2Na [M+Na]+: 319.1441, found: 319.1435.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([CH3:24])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=2)=[C:17]([CH3:24])[CH:16]=1
Reactant: COCc1oc(Br)cc1C(=O)OC
Reactant: Cc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COCc1oc(-c2ccc(F)cc2C)cc1C(=O)OC
Yield: 93.1 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)-3-furancarboxylate (2.5 g), 4-fluoro-2-methylphenylboronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (2.6 g, 92%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=S)[CH:8]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO.O>[OH:15][N:14]=[C:9]1[CH:8]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[S:11][S:10]1
Reactant: NO
Reactant: S=c1cc(-c2cnccn2)ss1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=c1cc(-c2cnccn2)ss1
Temperature: 65 °C
Yield: 72.6 %

Procedure:
A suspension of 5-(pyrazin-2-yl)-1,2-dithiole-3-thione (31.85 g.) in methanol (1,400 cc.) is heated at a temperature of about 65° C. Hydroxylamine hydrochloride (24 g.), followed by sodium acetate (35 g.) dissolved in water (75 cc.), are then added. The reaction mixture is then heated for 3 hours at a temperature of about 65° C. After cooling to a temperature of about 20° C., the insoluble product is filtered off and is then washed with methanol (4 × 100 cc.) and with carbon disulphide (4 × 100 cc.). The product is dissolved in dimethylformamide (300 cc.) at 100° C. and is then reprecipitated by adding water (600 cc.). After filtration and drying, 3-hydroxyimino-5-(pyrazin-2-yl)-1,2-dithiole (23 g.) melting at 262° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Cl.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][NH2:26]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:25]([C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])[N:26]=1)=[O:15]
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)cc1
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
4-(4-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (50.0 g, 185.8 mmol) prepared in Step 2 of Preparation 17 and 2,4-difluorophenylhydrazine hydrochloride (36.9 g, 204.4 mmol) were added to acetic acid (600.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 73.4 g of 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester as a yellow liquid.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11](=[O:33])[N:12]([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][N:14]=1)([CH3:9])([CH3:8])[CH3:7].C[N:35](CCN(C)C)C.[N-]=[N+]=[N-].[Na+]>C(OCC)(=O)C.O>[NH2:35][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH2:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)([CH3:24])[CH3:25])[C:11](=[O:33])[O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCO)cn1
Reactant: CN(C)CCN(C)C
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCN)cn1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (87 μL, 1.1 mmol, 1.1 equiv) dissolved in 2 mL ethyl acetate was added to a 20 dram vial. To this stirring mixture was added a mixture of tert-butyl-2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)-carbamate (414 mg, 1.1 mmol, 1.0 equiv), TMEDA (167 μL, 1.1 mmol, 1.1 equiv), and ethyl acetate (3 mL) in a dropwise manner. The reaction was stirred for 1 h. The reaction mixture was then filtered and washed with saturated sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The resultant solid was dissolved in DMF (4 mL), followed by the addition of sodium azide (139 mg, 2.1 mmol, 2.0 equiv). The reaction was stirred for 24 h, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in methanol, followed by the addition of 10% palladium on carbon (80 mg), potassium carbonate (100 mg). The reaction was stirred under 45 psi of hydrogen for 24 h, filtered, and concentrated to give tert-butyl 5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.