Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][CH2:14][C:15]([OH:54])([CH3:53])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[C:50]([CH3:52])[N:51]=[C:25]23)[CH2:20][CH2:19]1>O.C(OCC)(=O)C>[F:13][CH2:14][C:15]([OH:54])([CH3:53])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[C:50]([CH3:52])[N:51]=[C:25]23)[CH2:20][CH2:19]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CF)CC2)c2nc(C)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CF)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.17 g), sodium hydrogen carbonate (0.27 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.094 g) was added, and the mixture was stirred at 90° C. for 14 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.033 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.030 mL) were added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.066 g, 63%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]=[N+:10]=[N-:11])[CH2:3][CH2:2]1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:36]2[CH:40]=[CH:39][C:38](/[CH:41]=[CH:42]/[C:43]([NH:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[O:44])=[CH:37]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[CH:26].C(Cl)Cl>O.CC(O)(C)C>[O:48]1[CH2:49][CH2:50][CH2:51][CH2:52][CH:47]1[O:46][NH:45][C:43](=[O:44])/[CH:42]=[CH:41]/[C:38]1[CH:39]=[CH:40][N:36]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([C:25]3[N:11]=[N:10][N:9]([CH2:8][CH2:7][N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:26]=3)=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH:37]=1
Reactant: [N-]=[N+]=NCCN1CCOCC1
Reactant: C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3cn(CCN4CCOCC4)nn3)cc2)c1)NOC1CCCCO1
Yield: 27 %

Procedure:
To a stirred mixture of 2-morpholino-ethylazide (0.30 mmol) in water (2 ml) are added CuSO4 pentahydrate (0.02 mmol), sodiumascorbate (0.04 mmol) and (E)-3-[1-(4-Ethynyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (0.30 mmol) in t-BuOH (1 ml) at room temperature. The reaction mixture is stirred over night. After addition of DCM the organic phase is separated, evaporated under reduced pressure and purified by prep. HPLC yielding 0.081 mmol of the title compound.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[I:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1>CCOC(C)=O>[I:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]=[C:4]=[O:3])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1ccc(I)cc1[N+](=O)[O-]

Procedure:
To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0° C. was added a solution of the 4-iodo-2-nitroaniline (45.5 mmol) in EtOAc (200-500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 4-iodo-2-nitrophenylisocyanate as a yellow solid. This material was refluxed in a mixture of excess tert.-BuOH in CH2Cl2 for 2.5 h. Removal of the solvent left an orange solid which was purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
Reaction SMILES: [F:1]/[C:2](/[CH2:13]Br)=[CH:3]/[CH2:4][NH:5]C(=O)OC(C)(C)C.[OH:15][C:16]1[C:30]([Cl:31])=[CH:29][C:19]([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])=[CH:18][C:17]=1[Cl:32]>>[ClH:31].[NH2:5][CH2:4]/[CH:3]=[C:2](/[F:1])\[CH2:13][O:15][C:16]1[C:17]([Cl:32])=[CH:18][C:19]([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])=[CH:29][C:30]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)CBr
Reactant: O=C(NC1CCCCC1)c1cc(Cl)c(O)c(Cl)c1
Product: Cl
Product: NC/C=C(/F)COc1c(Cl)cc(C(=O)NC2CCCCC2)cc1Cl

Procedure:
(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-3,5-dichloro-N-cyclohexylbenzamide hydrochloride was synthesized from (E)-tert-butyl 3-fluoro-4-bromobut-2-enylcarbamate and 4-hydroxy-3,5-dichloro-N-cyclohexylbenzamide.
Reaction SMILES: [C:1]([OH:4])(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([NH2:22])[CH:9]=[CH:10][C:11]=1[S:12][CH:13]1[CH2:19][CH:18]2[N:20]([CH3:21])[CH:15]([CH2:16][CH2:17]2)[CH2:14]1>C(O)=O>[Cl:5][C:6]1[CH:7]=[C:8]([NH:22][CH:1]=[O:4])[CH:9]=[CH:10][C:11]=1[S:12][CH:13]1[CH2:14][CH:15]2[N:20]([CH3:21])[CH:18]([CH2:17][CH2:16]2)[CH2:19]1
Reactant: CC(=O)O
Reactant: CN1C2CCC1CC(Sc1ccc(N)cc1Cl)C2
Solvent: O=CO
Product: CN1C2CCC1CC(Sc1ccc(NC=O)cc1Cl)C2
Reaction time: 1.5 h
Yield: 13.7 %

Procedure:
A mixture of acetic acid (0.96 g) and formic acid (0.53 g) was heated under reflux for 2 hours. To this was added 3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylamine (265 mg) and heating continued for 1.5 hours. The crude mixture was placed on an SCX cartridge and eluted with methanol followed by 2M ammonia in methanol. The impure product was then subjected to flash chroamtography on silica gel (gradient elution with increasing percentage of methanol in chloroform) to yield material of 93% purity. Final clean up by preparative LC-MS gave 3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylformamide (40 mg)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH2:21]O)[CH:8]=[C:7]([Cl:23])[CH:6]=1.P(Br)(Br)[Br:26]>COCCOC>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([Cl:23])[CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH2:21][Br:26])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2CO)c1
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [3-chloro-5-(2-hydroxymethyl-4-nitro-phenoxy)-phenyl]-acetic acid methyl ester (2.4 g, 6.8 mmol) in DME (20 mL) was added phosphorus tribromide (0.97 mL, 10.2 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up with EtOAc and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.Cl.CC[Cl:23]>CC(C)=O.C(OCC)C>[ClH:23].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:13][CH:14]=1
Reactant: COc1ccc([C@H](CO)NC(=S)NC(C)(C)C)cc1
Reactant: CCCl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1ccc([C@@H]2CSC(N)=N2)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 2.5 g of N-(tert-butyl)-N′-[(1R)-1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea in 25 cm3 of aqueous 6N hydrochloric acid for 3 hours at a temperature in the region of 100° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. 15 cm3 of aqueous 1N sodium hydroxide and 5 cm3 of water are added to the residue obtained. The mixture is extracted with 20 cm3 of ethyl acetate and the organic phase is then concentrated as above. The product obtained is purified by chromatography, under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63μ; mass of silica 80 g), eluting with an ethyl acetate/methanol mixture (80/20 by volume), and collecting about 10 cm3 fractions. Fractions 10 to 16 are combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.23 g of a lacquer is obtained, the hydrochloride of which is prepared in the following way: the product is dissolved in 2.5 cm3 of acetone and 1 cm3 of diethyl ether, followed by addition thereto of 2 cm3 of 4.5N hydrochloric ether. A crystalline product precipitates. It is filtered off, washed 3 times with acetone and then dried at a temperature in the region of 40° C. under reduced pressure (10 Pa). 0.09 g of (−)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of a white solid melting at 236° C. (αD20=−79.6±1.3 at a concentration of 0.5% in methanol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[NH:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:17]>>[C:1]([C:5]1[CH:6]=[C:7]([C:12]([NH2:11])=[O:13])[C:8](=[CH:14][CH:15]=1)[C:9]([NH2:17])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)NC2=O
Agent: [OH-]
Product: CC(C)(C)c1ccc(C(N)=O)c(C(N)=O)c1
Reaction time: 3 h

Procedure:
A 4 liter conical flask was then charged with 137.4 grams (0.6757 mole) of 4-t-butylphthalimide and 2 liters of 29 percent ammonium hydroxide solution and the solution was stirred vigorously with a mechanical stirrer. After 3 hours, the creamy suspension was suction filtered and washed with a small amount of water. The faint green powder was dried at 120° C. for one day to yield 134.19 grams of 4-t-butylphthalamide, which exhibited a melting point of 172° to 175° C. The identity of the 4-t-butyl-phthalamide product was confirmed by IR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH:14]([C:17]1[CH:23]=[CH:22][C:20](N)=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C1C2C(CCCC2)CCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:20]2[CH:22]=[CH:23][C:17]([CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)c1ccc(N)cc1
Solvent: C1CCC2CCCCC2C1
Product: CC(C)c1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])cc1
Yield: 60.5 %

Procedure:
A mixture of 15 g of 4-chloro-1,2-dinitrobenzene, 10 g of 4-isopropylaniline and 25 ml of Decaline® is refluxed for 15 hours. The reaction mixture is concentrated under 0.01 mm Hg, the residue is taken up with water, extracted with ether, washed with a 1N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using iso ether as the eluent to give 13 g of the expected product, which is used as such in the next step.
Reaction SMILES: [Mg].[B:2]([O:7]C)(OC)[O:3]C.Br[C:10]([C:12]([F:15])([F:14])[F:13])=[CH2:11].Cl>O1CCCC1.O.C(OCC)C>[F:13][C:12]([F:15])([F:14])[C:10]([B:2]([OH:7])[OH:3])=[CH2:11]
Reactant: COB(OC)OC
Reactant: C=C(Br)C(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(B(O)O)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To magnesium turnings (5.83 g, 0.24 mol) in tetrahydrofuran (400 ml) was added dropwise trimethyl borate (68.13 ml, 0.6 mol). The reaction mixture was cooled to 0° C. and 2-bromo-3,3,3-trifluoropropene (20.75 ml, 0.2 mol) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred under nitrogen overnight. The reaction mixture was again cooled to 0 □C and hydrochloric acid (5M, 200 ml) was added dropwise, ensuring that the temperature of the solution remained below 10 □C. The reaction mixture was then stirred under nitrogen for 48 h. To the reaction mixture was added diethyl ether (100 ml) and water (200 ml) to give two phases. The aqueous layer was separated and extracted with diethyl ether (100 ml). The combined organic phases were washed with water (100 ml), dried (MgSO4) and concentrated in vacuo. To the residue was added cyclohexane (50 ml), resulting in precipitate formation. The precipitate was isolated by decanting the solution, washed with cyclohexane, and dried in vacuo to give Preparation 59 (2.62 g, 0.02 mol) as a white solid.
Reaction SMILES: [ClH:1].[CH:2]1[C:16]2=[C:17]3[C:9]([C:10]4[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[C:4]([CH2:18][NH:19][C:20]([CH3:25])([CH2:23]O)[CH2:21][OH:22])[CH:3]=1.C1C2=C3C(C4C2=CC=CC=4)=CC=CC3=C(C=O)C=1.CC(N)(C)CO>CO.CCOCC>[ClH:1].[CH:2]1[C:16]2=[C:17]3[C:9]([C:10]4[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[C:4]([CH2:18][NH:19][C:20]([CH3:25])([CH3:23])[CH2:21][OH:22])[CH:3]=1
Reactant: CC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2
Agent: CC(C)(N)CO
Agent: Cl
Agent: O=Cc1ccc2c3c(cccc13)-c1ccccc1-2
Solvent: CO
Solvent: CCOCC
Product: CC(C)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2

Procedure:
Using the reductive amination procedure outlined in 1D, 3-fluoranthenecarbaldehyde (1A) and 2-methyl-2-aminopropanol (Aldrich) gave 2-((3-fluoranthenylmethyl)-amino)-2-methyl-1-propanol hydrochloride, mp 288°-290° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: C1(C)C=CC([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=CC=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[Na])(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:19]1([CH3:20])[CH:18]=[CH:17][CH:22]=[CH:21][C:14]=1[C:11]1[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: Ic1ccccc1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccccc1-c1ccc(N)cc1

Procedure:
10.0 g (50.7 mmols) of N,N-di(p-toluyl)amine (31b), 10.3 g (50.7 mmols) of 4-iodobenzene, 5.85 g (60.8 mmols) of t-BuONa, 300 mg (1.34 mmols) of Pd(CH3CO)2 and 1.50 g (5.71 mmols) of triphenylphosphine were dissolved in xylene and refluxed in an atmosphere of nitrogen for 4 hours.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Reactant: c1cn[nH]c1
Product: Cc1csc2nc(-n3cccn3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:34][C:35]1[NH:39][N:38]=[C:37]([NH2:40])[CH:36]=1.[I-].[K+]>CN(C=O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:4]2[N:3]=[C:2]([NH:40][C:37]3[CH:36]=[C:35]([CH3:34])[NH:39][N:38]=3)[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=3)[N:5]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(C(F)(F)F)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To (4-chloro-7-(trifluoromethyl)quinazolin-2-yl)(4-fluorophenyl)methanone (1 g, 2.82 mmol) in DMF (10 mL) were added DIEA (0.49 mL, 2.82 mmol), 5-methyl-1H-pyrazol-3-amine (823 mg, 8.47 mmol), and potassium iodide (468 mg, 2.82 mmol) and the mixture was stirred at rt for 2 h. To the reaction mixture was added water followed by extraction with EtOAc. The organic phases were dried over sodium sulfate. The solvent was concentrated and the residue was dried under high vacuum overnight. The crude solid (240 mg) was purified on reverse-phase preparative HPLC (elution gradient of 40-90% acetonitrile in water with 0.05% acetic acid) to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(trifluoromethyl)quinazolin-2-yl)methanone as a yellow solid (40 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.2 (s, 3H) 6.55 (s, 1H) 7.35-7.5 (m, 3H) 7.9-8.0 (m, 1H) 8.05-8.3 (m, 4H) 11.1 (s, 1H) 12.25 (s, 1H) LC-MS (ESI) m/z 416 (M+H)+.
Reaction SMILES: [CH:1]1[N:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-])=O)=[CH:14][CH:13]=3)[CH2:7]2)[N:3]2[CH2:22][CH2:23][CH2:24][C:2]=12.O.[Cl-:26].[Ca+2].[Cl-]>C(O)C.[Fe]>[ClH:26].[CH:1]1[N:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[N:17]=[C:16]([NH2:18])[C:15]([NH2:19])=[CH:14][CH:13]=3)[CH2:7]2)[N:3]2[CH2:22][CH2:23][CH2:24][C:2]=12
Reactant: [Cl-]
Reactant: Nc1nc(N2CCCC(c3ncc4n3CCC4)C2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: Cl
Product: Nc1ccc(N2CCCC(c3ncc4n3CCC4)C2)nc1N
Temperature: 70 °C

Procedure:
6-(3-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)piperidin-1-yl)-3-nitropyridin-2-amine (20 mg, 0.1 mmol) was dissolved in ethanol (0.5 mL) and water (0.1 mL) under nitrogen. Then iron 200 mesh (27 mg, 0.5 mmol) and calcium chloride (3.3 mg, 0.03 mmol) were added and the mixture was heated to 70° C. for 18 h. The reaction mixture was cooled to room temperature followed by filtration through a 0.2 μm nylon syringe filter and rinsing with ethanol (0.5 mL) to afford the title compound. The filtrate was carried on to the next step without further purification. MS (AP+) (M+H) 299.1; LCMS retention time: 0.44 minutes (Method L)
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C@@H:47]2[CH2:49][O:48]2)=[CH:41][C:40]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52])C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:49][C@H:47]([OH:48])[CH2:46][O:45][C:42]3[CH:43]=[CH:44][C:39]([OH:38])=[C:40]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:41]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1
Yield: 19 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.516 g, 1.2 mmol) was reacted with N-{2-(benzyloxy)-5-[(2S)oxiranylmethoxy]phenyl} methanesulfonamide (prepared according to patent WO9604233) (0.38 g, 1.09 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.15 g, 0.207 mmol).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: ClCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)-(1-ethoxycarbonyl-piperidin-4-yl)amine (1.5 g, 5.2 mmol) in tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice-bath. Add sodium hydride (0.25 g, 60% n in oil, 6.24 mmol). After 90 minutes, add 2-(chloromethyl)furan (0.90 g, 7.8 mmol). Warm to ambient temperature. After 60 hours, quench by the addition of ice and then a saturated aqueous ammonium chloride solution. Evaporate to remove most of the tetrahydrofuran, dilute with ethyl acetate, and extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine: Rf=0.29 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][C:8](=[O:17])[N:7]=[C:6]1[S:18]C.[NH4+]=S.N1C=CC=CC=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][C:8](=[O:17])[NH:7][C:6]1=[S:18]
Reactant: COCCn1c(-c2ccccn2)cc(=O)nc1SC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: COCCn1c(-c2ccccn2)cc(=O)[nH]c1=S
Yield: 3.2 %

Procedure:
A mixture of crude 1-(2-methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one (100 mg, 0.36 mmol), ammonium sulfide solution (0.2 mL, 0.64 mmol) and pyridine (0.2 mL) was stirred in dioxane (2 mL) at 70° C. for 4 hours. The reaction mixture was diluted with water (10 mL), basified with 2M NaOH and washed with dichloromethane (3×10 mL). The aqueous layer was acidified to pH 6 with 2M HCl and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (3×10 mL), brine (3×10 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by mass directed automatic purification using an acidic method to give the product as a brown solid (3 mg, 3%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=[O:20].[K+].[K+]>CC(C)=O.CCOC(C)=O.O>[CH2:11]([O:20][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C(COCc1ccccc1)c1ccccc1

Procedure:
A mixture of 2′-hydroxyacetophenone (68.1 g, 0.500 mol), benzylbromide (65.4 ml, 94.1 g, 0.550 mol) and K2CO3 (103 g, 0.750 mol) in acetone (1.00L) was stirred and heated to reflux overnight. The resulting mixture was concentrated under reduced pressure to obtain a residue. The obtained residue was dissolved in the mixture of AcOEt and water and then extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude material. The crude material was purified by distillation under reduced pressure to give starting compound 1A as a colorless oil (100 g, yield 88%).