Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21](F)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (91.6 μl, 0.722 mmol) and triethylamine (101 μl, 0.722 mmol) were added to a dimethyl sulfoxide (2 ml) solution of ethyl 2-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-1,3-thiazole-4-carboxylate (I-197) (147 mg, 0.361 mmol), followed by stirring in an oil bath at 100° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml) and washed with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=100:1→100:3), and the obtained yellow solid was purified in slurry with isopropanol (3 ml) to obtain the entitled compound (120 mg, 66.3%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1.Cl[C:26]1[C:31](NS(N(C)C)(=O)=O)=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.BrC1C=CC2N(C(I)=CN=2)C=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:17][C:14]1[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:30]4[CH:29]=[CH:28][N:27]=[CH:26][CH:31]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:16][N:15]=1
Reactant: CN(C)S(=O)(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)cnc1Cl
Reactant: CN(C)S(=O)(=O)Nc1cc(-c2cnc3ccc(Br)cn23)cnc1Cl
Agent: [Fe+2]
Agent: Brc1ccc2ncc(I)n2c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Nc1cc(-c2cnc3ccc(-c4ccncc4)cn23)cnc1Cl
Temperature: 110 °C

Procedure:
N-(5-(6-bromoimidazo[1,2-a]pyridin-3-yl)-2-chloropyridin-3-yl)dimethylaminosulfonamide. To a 5 mL microwave tube was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)dimethylaminosulfonamide (0.200 g, 0.553 mmol), 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.214 g, 0.664 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.020 g, 0.028 mmol), sodium carbonate (0.691 mL, 1.383 mmol), and dioxane (3 mL). The resulting mixture was sealed and underwent microwave heating at 110° C. for 15 min. The solvent was removed. The residue was partitioned between pH 7 buffer (1M TRIS-HCL) and DCM. The aqueous layer was extracted more with DCM (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, 12 g SiO2, hexanes:acetone=80%:20%, Flow=30 mL/min). The solvent was removed in vacuo to afford the desired product as brown solid (180 mg). MS (ESI pos. ion) m/z: 429.7. Calcd exact mass for C14H13BrClN5O2S: 428.9. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.94 (s, 6H) 7.36 (d, J=9.65 Hz, 1H) 7.63 (d, J=9.50 Hz, 1H) 7.79 (s, 1H) 8.09 (s, 1H) 8.34 (s, 1H) 8.42 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([CH3:26])=[N:9][C:10]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4].C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>>[C:31]([O:1][CH:2]([C:7]1[C:8]([CH3:26])=[N:9][C:10]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.3 %

Procedure:
To a solution of methyl 2-hydroxy-2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.135 g; 0.380 mmol) in tert-butyl acetate (1.5 mL; 11.23 mmol) under nitrogen atmosphere was added perchloric acid 70% (0.049 mL; 0.570 mmol) and the reaction was stirred at room temperature for 2 days. The reaction was quenched by adding a saturated solution of sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulphate, filtered a,d concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-40%) in heptane furnished 0.063 g (40%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:17][CH:18]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
(3,3,3-Trifluoropropyl)malononitrile (0.6 g) and 2-chloro-5-chloromethylpyridine (0.6 g) were dissolved in N,N-dimethylformamide (15 ml), potassium carbonate (0.51 g) was added thereto, and the mixture was stirred overnight at room temperature. Then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water, saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained was subjected to silica gel column chromatography to give 0.62 g of 2-((6-Chloro-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (4)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=S)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[NH2:22])[NH:18][C:17](=[O:23])[C:16]2([CH3:25])[CH3:24].C(N(CC)CC)C.C(OCC)C>ClCCl.C(O)C>[CH3:24][C:16]1([CH3:25])[C:15]2[C:19](=[CH:20][C:21]3[NH:22][C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:12][C:13]=3[CH:14]=2)[NH:18][C:17]1=[O:23]
Reactant: COc1ccc(N=C=S)cc1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2nc3cc4c(cc3[nH]2)NC(=O)C4(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3 ml. 4-Methoxyphenyl isothiocyanate are added dropwise to a solution of 3.8 g. 5,6-diamino-3,3-dimethylindolin-2-one in 20 ml. dry ethanol. The reaction mixture is stirred for 3 hours at 60° C., the solvent is removed in a vacuum, the residue is suspended in water and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulphate, filtered and the solvent removed in a vacuum to give 7.5 g. of residue, 6.8 g. of which are dissolved in 1 liter dichloromethane. 8 ml. Triethylamine and 16 g. mercurous chloride are added thereto and the reaction mixture boiled under reflux for 3 days. The solvent is removed in a vacuum, the residue is suspended in 100 ml. ethanol and 30 ml. concentrated hydrochloric acid are added thereto, followed by saturation with hydrogen sulphide. The reaction mixture is heated under reflux and the precipitated mercury sulphide is filtered off and then washed with hot ethanol. The filtrate is evaporated to dryness in a vacuum, the residue is dissolved in 100 ml. water, insoluble components are filtered off, the filtrate is rendered alkaline with 2N ammonia solution, the base is filtered off with suction and then washed with water. The product is purified over a silica gel column (elution agent 1,1,1-trichloroethane/methanolic ammonia 15:1 v/v). The appropriate fractions are evaporated in a vacuum, the oil obtained is taken up in hot ethanol, diethyl ether is added thereto until turbidity commences and then left to crystallise. There are obtained 2.8 L g. of the title compound; m.p. 286°-288° C.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:16][N+:17]([CH3:26])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>>[CH3:26][N:17]([CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5]1[N:1]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:2]=[CH:3][CH:4]=1)[CH3:16]
Reactant: NC(=S)c1ccccc1-n1cccc1
Reactant: Cc1ccccc1C=[N+](C)C
Agent: [Cl-]
Product: Cc1ccccc1C(c1cccn1-c1ccccc1C(N)=S)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-thiobenzamide and dimethyl-(2-methyl-benzylidene)-ammonium chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:13]C(O)=O.CC[N:19](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C[Si](C)(C)[O-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:13][NH2:19]
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1c(Cl)cc(Cl)cc1C(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: Cc1ccccc1
Product: NCc1c(Cl)cc(Cl)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-6-trifluoromethylphenylacetic acid (0.36 mmol) in 3 mL toluene were added Et3N (0.44 mmol) and DPPA (0.36 mmol). The reaction mixture was heated to 110° C. for 3 h, cooled to 0° C. and a solution of potassium trimethylsilanolate (0.73 mmol, 1M in THF) was added. After stirring at RT for 30 min, an aqueous solution of 10% citric acid was added and the mixture was extracted twice with Et2O. The aqueous phase was basified with 1M NaOH solution and extracted 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-methyl-1H-pyrazole.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCCCO)(=O)C=C.C[C@@:19]12[CH:27]([C:28](C([O-])=O)=C)[CH2:26][C@H:22]([C:23]1([CH3:25])[CH3:24])CC2.C(OCCCC)(=O)C=C>>[CH3:28][C:27]([CH2:19][C:23]([CH3:25])([CH3:24])[CH3:22])=[CH2:26].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C(C(=O)[O-])C1C[C@H]2CC[C@@]1(C)C2(C)C
Agent: C=CC(=O)OCCCC
Agent: C=CC(=O)OCCCO
Solvent: C=Cc1ccccc1
Product: C=C(C)CC(C)(C)C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Charge 1 was added to a 4-liter stirred stainless steel pressure reactor. The reactor was pressurized with nitrogen providing a 5 psig pad on the reactor. The agitation on the reactor was set at 500 rpm and the reactor temperature was adjusted to 150° C. Charge 2 was added to the reactor at an addition rate of 36 grams/hour over a 2.5 hour period. After 15 minutes Charge 3 was added to reactor at an addition rate of 1000 grams/hour over a 2 hour period. During the monomer addition the temperature was maintained at 150° C. and 60 PSI. After Charges 2 and 3 were in the reactor, the reaction mixture was held for 2 hours. The reactor was than cooled to 25° C. GC analysis of the reaction mixture showed that all acrylates and styrene were reacted. The final solids of the resulting polymer was 83.12% determined at 110° C. for one hour. The copolymer had Mn=1400 and Mw/Mn=2.4. The 13C NMR spectrum was consistent with a molar copolymer composition of 22.1% diusobutylene, 35.0% hydroxypropyl acrylate, 15.6% isobornyl-acrylate, 7.8% styrene, and 19.5% butyl acrylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:5][CH2:4][N:3]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1COCC1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:9])[CH2:5][CH2:4][N:3]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a pre-dried RB flask, 1-tert-butyl 4-(9H-fluoren-9-ylmethyl) 2-oxopiperazine-1,4-dicarboxylate (6.5 g, 15.39 mmol) was dissolved in CH2Cl2 (150 mL) and THF (15 mL) under N2 and was cooled down to −78° C. DIBAL-H (23.08 mL, 23.08 mmol) was added slowly. Let reaction stir at −78° C. for 2 hours. Then saturated Rochelle's salt water solution (150 mL) was added to quenched reaction. Reaction was slowly warmed up to room temperature. Then it was passed through a Celite® pad. Filtering pad was washed with ether (100 mL×2). Then layers were separated and aq. layer was extracted with 50 mL of EtOAc twice. Organic phases were combined and were washed with water and brine (50 mL) respectively. Then it was passed anhydrous Na2SO4. Concentration gave crude product as white solid that was used directly in next step. LC/MS: (M+23)+=447.16
Reaction SMILES: [C:1]([N:5]1[CH2:10][C:9](OS(C(F)(F)F)(=O)=O)=[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)C>[C:1]([N:5]1[CH2:10][C:9]([C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][C:29]=2[F:31])=[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:7][CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CN(C(C)(C)C)CC1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccc(F)cc2F)CN(C(C)(C)C)CC1
Temperature: 80 °C
Yield: 60.1 %

Procedure:
The product of step D (5.05 g; 14.4 mmol), 2,4-difluorophenylboronic acid (2.85 g; 18.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.589 g; 0.7 mmol) were combined and dissolved a 2:1 mixture of toluene:ethanol (54 mL). The reaction was heated to 80° C. followed by the dropwise addition of 2 M aqueous sodium carbonate over 10 min. The reaction was maintained at 80° C. for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered concentrated in vacuo. The crude residue was purified on silica gel using a gradient elution (30%→40%→60% ethyl acetate/hexane) which furnished the title compound (2.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][CH3:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:21]([CH2:23][CH2:24][N:25]3[CH2:28][CH:27]([F:29])[CH2:26]3)[CH:22]=2)=[CH:14][C:13]=1[C:36]([F:39])([F:38])[F:37].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:9]([C:3]1[C:4]([NH2:8])=[N:5][CH:6]=[N:7][C:2]=1[N:33]1[CH2:32][CH2:31][CH:30]([C:20]2[N:21]([CH2:23][CH2:24][N:25]3[CH2:28][CH:27]([F:29])[CH2:26]3)[CH:22]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[C:13]([C:36]([F:39])([F:37])[F:38])[CH:14]=3)[N:19]=2)[CH2:35][CH2:34]1)[CH3:10]
Reactant: Fc1ccc(-c2cn(CCN3CC(F)C3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: CCc1c(N)ncnc1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)C2)CC1
Reaction time: 1 h
Yield: 19.3 %

Procedure:
The reaction mixture of 6-chloro-5-ethyl-pyrimidin-4-ylamine (50.00 mg; 0.32 mmol; 1.00 eq.), 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (138.05 mg; 0.33 mmol; 1.05 eq.) and DIEA (65.77 mg; 0.48 mmol; 1.50 eq.) in DMSO (1.5 ml) was placed in microwave at 125° C. for 1 hr. found small amount desired, mostly was sm, 140° C. for another 1 hr, more product formed, 150° C. for another 1 hr, purified the product by HPLC, collected title compound 33 mg, yield 16%. LC-MS (M+1=536, obsd.=536).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@@:12]([CH:24]([F:26])[F:25])([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[F:23])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[F:23])([CH:24]([F:26])[F:25])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)COC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of [(R)-5-difluoromethyl-5-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (8 g, 19.23 mmol) in MeOH (56 mL) was added Pd(OH)2/C (20%, 50% water, 0.8 g). The atmosphere in the reactor was replaced by hydrogen (1 bar), then the reaction mixture was stirred at 20° C. for 5 h, filtered through Micro-crystals cellulose and concentrated. The crude product was recrystallized from MeOH and water to provide the title compound as a white solid: ESIMS: 360.1521; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 6.83 (dd, 1H), 6.74 (m, 1H), 6.50 (m, 1H), 6.22 (t, 1H), 4.95 (s, 2H), 4.46 (dd, 2H), 4.03 (m, 1H), 3.84 (m, 1H), 1.42 (s, 9H).
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1)=O)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[F:27][C:22]1[CH:21]=[C:20]([C@H:18]2[NH:9][C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][CH2:17]2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: COC(=O)[C@@H](CCCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2ccc(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 80.4 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (20 mL) was added to a solution of methyl(R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (3.8 g) in ethyl acetate (20 mL), and the reaction solution was stirred at room temperature for 5.5 hours. The reaction solution was concentrated under reduced pressure. Then, ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (50 mg) was added to a solution of the resulting residue in methanol (20 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 2.1 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Br[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH3:19][C:18]([CH3:20])=[CH:17][CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: CC(C)=CCCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitroimidazole (3.0 g, 27 mmol) in dry dimethylformamide (25 mL), was added anhydrous sodium bicarbonate (4.2 g, 50 mmol) followed by 5-bromo-2-methyl-2-pentene (5.0 g, 30.67 mmol). The reaction mixture was heated at 60-70° C. with stirring under nitrogen for 16 hours. Solvent dimethylformamide and the unreacted bromide were removed under reduced pressure (<1 mm) at 50-60° C. to yield a paste which was dissolved in water (50 mL) and extracted with ethyl acetate (5×50 mL). The combined organic extracts were dried and concentrated to give a brown oil which was recrystallized from petroleum ether (b.p. 40-60° C.) to yield a yellow solid. Yield: 4.8 g, m.p. 51-52° C. 1H NMR (CDCl3) δ1.55 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.7 (q, 2H, olefinic CH2), 4.5 (t, 2H, N—CH2), 5.2 (t, 1H, olefinic H), 7.1 (s, 1H, imidazole H), 7.2 (s, 1H, imidazole H). M.S. [M+H]+ 196, [M+NH4]+ 213.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]=[C:16]([CH3:25])[C:15]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][N:8]2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]=[C:16]([CH3:25])[C:15]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Reactant: N#Cc1c[nH]c2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Cl)cc2c(-n2cc(C#N)c3ccc(Br)cc32)c1C

Procedure:
A solution of 6-bromo-1H-indole-3-carbonitrile (0.5 g, 2.26 mmol), 4,6-dichloro-2,3-dimethylquinoline (0.56 g, 2.49 mmol) and cesium carbonate (2.21 h, 6.79 mmol) in DMF (11.2 mL) was heated at 140° C. overnight. After this time the solvent was evaporated in vacuo and the residue was purified by flash column chromatography to give 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-3-carbonitrile as white solid. Mass Spectrum (ESI) m/e=411 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([CH3:22])[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1>>[CH3:22][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccccc1C=O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: Cc1ccccc1CN1CCN(c2cc(=O)[nH]cn2)CC1

Procedure:
6-[4-(2-Methyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and o-tolualdehyde. Mass spectrum (ES) MH+=285.