Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1.C(O)C.Cl.[H-]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:20]2[CH2:19][CH2:18][NH:17][C:16](=[O:15])[CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1CNCCN1
Agent: Cl
Agent: [H-]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCNC(=O)C2)CC1
Reaction time: 0.75 h
Yield: 34.1 %

Procedure:
A mixture of 1-t-butoxycarbonyl-4-oxopiperidine (2.985 g) and 2-oxopiperazine (1.5 g) was dissolved in methanol (25 ml), and molecular sieves 3A (2.5 g) and 1N ethanol-hydrochloric acid (2.5 ml) were then added, followed by stirring for 45 minutes. Cyanoboronsodium hydride (945 ml) was divided into three portions and they were then separately added to the solution under ice-cooling, followed by stirring 5 hours at room temperature. After insolubles were removed with sellaite, the filtrate was then concentrated. To the resultant residue, a saturated sodium hydrogencarbonate solution was added, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution and then dried over magnesium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography (300 g, chloroform:methanol=30:1 to 10:1) to give 1.448 g of 4-(1-t-butoxycarbonylpiperidin-4-yl)-2-oxopiperazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(CC)CC>O.[Cl-].[Na+].O>[C:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(-c2ccccc2)c1
Yield: 92.6 %

Procedure:
3-Bromobenzonitrile (91 mg, 0.5 mmol), phenylboronic acid (91 mg, 0.75 mmol), and Pd(dtbpf)Cl2 (6 mg, 0.01 mmol) were added to a reaction tube equipped with a magnetic stir bar. Under a positive flow of argon while stirring, surfactant solution (1.0 mL, 2 wt % TPGS-M-PEG-750 in water), and Et3N (0.21 mL, 1.5 mmol) were added by syringe and stirred vigorously for 2 h. The reaction mixture was then diluted with brine and extracted with EtOAc. The solution obtained was dried over anhydrous MgSO4 and concentrated by rotary evaporation. The residue was purified by flash column chromatography eluting with 20% CH2Cl2/hexanes to afford the product (83 mg, 93%) as a slightly yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[SH:16])=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.O>CCCCCC.C(OCC)(=O)C>[SH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(O)cc1)c1ccccc1S
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Oc1ccc(Cc2ccccc2S)cc1
Yield: 87.5 %

Procedure:
To a mixture of 0.954 g (4-hydroxyphenyl)(2-mercaptophenyl)methanone (D) (4.0 mmol), 1 ml triethylsilane was added 5 ml TFA. The mixture was stirred at ambient temperature for 1 hour before water was added. The reaction mixture was extracted with ethyl acetate (2×70 ml), brine, dried over magnesium sulfate, filtered and concentrated. Flash silica chromatography (hexane:ethyl acetate 80:20) afforded 0.786 g product (3.5 mmol, 88% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC.[Cl-].[NH4+]>CCCCCC.CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[O:17])=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(CCOC2CCCCO2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 11.3 g of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene and 100 ml of tetrahydrofuran was cooled to −78° C., to which 25.9 ml of 1.56 M solution of n-butyl lithium in n-hexane was added dropwise over 15 minutes. After stirring at −78° C. for 1 hour, 4.2 ml of N,N-dimethylformamide was added dropwise at the same temperature over 15 minutes. After further stirring at −78° C. for 1 hour, 100 ml of saturated aqueous ammonium chloride solution was added, and the stirring was further continued until the reaction mixture came to room temperature. The reaction mixture was extracted twice with 200 ml of ethyl acetate, and the ethyl acetate layers were combined, washed three times with saturated aqueous ammonium chloride solution, and washed with saturated aqueous sodium chloride solution. The combined ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. This residue was subjected to silica gel chromatography, which afforded 7.20 g (yield, 78%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-benzaldehyde, nD24.5 1.5311.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:38])[CH2:9][N:10]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])[C:12]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH:35]([F:37])[F:36])=[N:11]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].O>CN(C=O)C.C(OCC)(=O)C>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([O:34][CH:35]([F:36])[F:37])=[C:27]([C:12]2[C:13]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:14][N:10]([CH2:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:3][CH2:4]3)=[O:38])[N:11]=2)[CH:32]=1
Reactant: NC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (126 mg, 0.24 mmol) in DMF (3 mL) was added potassium carbonate (76 mg, 0.55 mmol), ethyl 2-bromoacetate (0.03 mL, 0.27 mmol). The resulting mixture was stirred at 25° C. for 1 h and diluted with 100 mL of ethyl acetate. Water (50 mL) was added. Phases were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: Xbridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 20% B to 85% B in 10 min; 254 nm. This resulted in 29.3 mg (98%) of ethyl 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]acetate as a white solid. LCMS (Method 25) [M+H]+=631.2, RT=1.89 min. 1H NMR (400 MHz, CD3OD-d4) δ: (ppm) 8.98 (d, 1H, J=6.8 Hz), 8.53-8.52 (m, 2H), 8.25 (s, 1H), 7.58 (d, 1H, J=2.4 Hz), 7.44 (dd, 1H, J=2.4, 8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.09 (dd, 1H, J=4.4, 6.8 Hz), 6.51 (t, 1H, J=73.6 Hz), 5.20-5.13 (m, 2H), 4.32 (d, 1H, J=13.2 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.91 (d, 1H, J=13.2 Hz), 3.36 (s, 2H), 3.21-3.09 (m, 1H), 2.78-2.68 (m, 2H), 1.94-1.83 (m, 2H), 1.34-1.22 (m, 2H), 1.16 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(C1C=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=CC=1)C.[CH3:23][N:24]1[CH:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1.[Cl:35][C:36]1[C:43]([CH2:44][CH3:45])=[CH:42][C:39]([CH:40]=[O:41])=[C:38]([F:46])[CH:37]=1>>[Cl:35][C:36]1[C:43]([CH2:44][CH3:45])=[CH:42][C:39]([CH:40]([C:28]2[N:24]([CH3:23])[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[OH:41])=[C:38]([F:46])[CH:37]=1
Reactant: Cn1cnc(-c2ccccc2)n1
Reactant: CCc1cc(C=O)c(F)cc1Cl
Agent: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Product: CCc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1Cl
Yield: 90.2 %

Procedure:
According to the procedure for Intermediate 370.2, 1-methyl-3-phenyl-1H-1,2,4-triazole (80 mg, 0.50 mmol) and Intermediate 390.2 (105 mg, 0.55 mmol) afforded 156 mg of Intermediate 390.3 as a white solid. LCMS 346.26 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC3=O)cc2C1
Agent: Cl
Product: O=C1CCCN1c1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-(2-oxo-pyrrolidin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 203.4 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:23])[NH:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)NC(Cc1ccccc1)C(=O)O
Yield: 96.9 %

Procedure:
A solution of methyl 2-(N′-(4-chlorophenyl)ureido)-3-phenylpropanoate (2.8 g) obtained in Example 1a) and 1 N sodium hydroxide (20 ml) in methanol (20 ml)-THF (10 ml) was mixed at room temperature for 15 hours, and the reaction solution was concentrated under reduced pressure. The solution was acidified by adding 1 N hydrochloric acid to the concentrated solution, and then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as colorless powder (2.6 g, 95%).
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: OB(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1ccco1
Temperature: 105 °C
Yield: 15.6 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (400 mg, 1 mmol), furan 2-boronic acid (285 mg, 1.5 mmol) and Pd(Ph3)2Cl2 (50 mg) were taken up in 13 mL of degassed dioxane in a screw cap pressure flask. Sodium bicarbonate (2 mL of 2M aqueous solution) was added, and the reaction mixture was heated to 105° C. for 40 hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (3% to 5% MeOH in methylene chloride with 1% ammonium hydroxide) to yield 53 mg of 5-(5-Furan-2-yl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. (M+H)=339. Mp=253.7-254.6° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[NH:9][C:8]2=O)(=[O:3])[CH3:2].CN(C=O)C.O=S(Cl)[Cl:37]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[Cl:37])(=[O:3])[CH3:2]
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)[nH]c(=O)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Cl)c2cc1OC(C)=O
Temperature: 25 °C

Procedure:
To a mixture of 2-[(3-phenyl)phenyl]-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.6 g, 9.32 mmole) in SOCl2 (40 mL) was added DMF (1 mL) and the reaction was stirred at reflux for 16 h. The mixture was cooled to RT and then the volatiles were removed in vacuo. The crude product was dissolved in CHCl3 (300 mL) and washed with saturated NaHCO3 solution (3×150 mL), water (2×150 mL) and brine (1×150 mL) and dried with Na2SO4. The solution was concentrated in vacuo to yield 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.0 g, 9.88 mmole). HPLC retention time 11.12 mins. (5-95-13 method).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.[CH3:26][O:27][C:28]1C=CC(CN)=[CH:30][CH:29]=1>>[NH2:3][N:4]([CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH2:5][C:6]1[CH:2]=[CH:1][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: COc1ccc(CN)cc1
Agent: CS(=O)(=O)O
Product: COc1ccc(CN(N)C=NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The compound of Example 6 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 4-methoxybenzylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 333.41; found mol. wt. (M+H) 334.2; 667.0 (Dimer)
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:12]([CH3:21])[C:11]2=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:12]1[N:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]2)[C:11]1=[O:22]
Reactant: CN1N=C(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1N=C(c2ccccc2)C2(CCCNC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of a racemic mixture of 3-Methyl-4-oxo-1-phenyl-2,3,7-triaza-spiro[4.5]dec-1-ene-7-carboxylic acid tert-butyl ester (110 mg, 0.32 mmol) in DCM (5 ml) was added TFA (0.5 ml). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was applied to a 1 g SCX-2 cartridge. The impurities were eluted with 1:1 DCM:MeOH, followed by 0.05M ammonia in 1:1 DCM:MeOH. The product was eluted with 1M ammonia in 1:1 DCM:MeOH and the clean fractions were concentrated in vacuo to afford the title compound. No further purification was performed on the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[Br-].[Li+]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Reactant: O=c1cc(Br)cc[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)C(Cc1ccccc1)n1ccc(Br)cc1=O
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
544 mg (3.13 mmol) of 4-bromopyridin-2(1H)-one and 845 mg (3.3 mmol) of ethyl 2-bromo-3-phenylpropanoate (racemate) in the presence of 1.15 eq. of sodium hydride and 2.3 eq. of lithium bromide were reacted according to General Method 4C (stirred at 65° C. for 1.5 h). Yield: 572 mg (51% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:42])[CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][C:33](=[O:35])[O:32][N:31]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:36][CH2:37][CH3:38])[N:12]3[N:39]=[CH:40][N:41]=[C:11]23)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:42])[CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][C:33](=[O:35])[O:32][N:31]=4)=[CH:22][CH:23]=3)=[C:13]([CH2:36][CH2:37][CH3:38])[N:12]3[N:39]=[CH:40][N:41]=[C:11]23)=[CH:6][CH:7]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)c2ccc(F)cc2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)c2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A mixture of 4-[2-(4-fluorophenyl)-2-hydroxyethyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.31 g), Dess-Martin reagent (0.35 g) and acetonitrile (10 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, 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. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.2 g, 65%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH2:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([Cl:13])[CH:5]=1)([O-])=O.C(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.[Fe]>[Cl:11][C:8]1[C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=[C:6]([Cl:13])[C:7]=1[Cl:12]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Cl
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(Cl)c(Cl)c1N
Temperature: 0 °C
Yield: 70.8 %

Procedure:
6-Nitro-2,3,4-trichloroaniline (17.6 g, 72.8 mmol), iron powder (140 g, 250 mmol), and ethanol (400 mL) were combined and the resulting suspension was cooled to 0° C. Concentrated hydrochloric acid (37%, 93 mL, 1.14 mol) was added dropwise over a period of 15 min by means of an addition funnel. When the addition was complete, the resulting suspension was heated to reflux for 3.5 h, after which time it was allowed to cool to room temperature and was subsequently diluted with water (2 L). The pH of the mixture was adjusted to approximately 8 by the slow addition of sodium carbonate. The product was extracted with ethyl acetate (2 L), dried over magnesium sulfate and the solvents were removed under reduced pressure by rotary evaporation. The product was further purified by silica gel chromatography using 65:35 hexane/ethyl acetate to afford 10.9 g (72%) of a tan solid; m.p. 113-115° C. Anal. Calcd for C6H5Cl3N2: C, 34.08; H, 2.38; N, 13.25. Found: C, 34.14; H, 2.41; N, 13.18.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:28])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6][C:5]1=[O:28])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)n1c(=O)ncc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 68.4 %

Procedure:
Prepared from 200 mg (0.52 mmol) of 1-isopropyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 235 mg (2.10 mmol) of potassium tert-butoxide in 10 mL of tetrahydrofuran. The semi-solid is triturated in 14 mL of 1:1 diethyl ether/hexane, and the powder is collected and dried to give 135 mg (68%) of the title compound:
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:33][N:34]1[C:38]([C:39]([C:41]2[CH:42]=[N:43][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:46]=2)=[O:40])=[CH:37][N:36]=[CH:35]1>C1COCC1>[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:38]3[N:34]([CH3:33])[CH:35]=[N:36][CH:37]=3)([C:41]3[CH:42]=[N:43][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:45][CH:46]=3)[OH:40])=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2c(C)cc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.6 M in hexane; 1.84 mL, 2.936 mmol) was added dropwise to a suspension of the 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxy-8-methylquinoline (1 g, 2.26 mmol, Intermediate 19: step b) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (0.63 g, 2.49 mmol, Intermediate 36: step c) in dry THF (23 mL) at −78° C. over a 2 minute period. After complete addition stirring was continued at −78° C. for 10 minutes then warmed in an ice bath to 0° C. The mixture was stirred for 1 hour then quenched with saturated aqueous NH4Cl and warmed to room temperature. After stirring for 10 minutes layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, evaporated in vacuo and chromatographed (0-5% MeOH in acetonitrile) to provide the title compound as an amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.00-8.07 (m, 1H), 7.92-7.99 (m, 2H), 7.87 (s, 1H), 7.72 (d, J=8.6 Hz, 3H), 7.57 (s, 1H), 7.33 (d, J=9.1 Hz, 2H), 7.16 (s, 1H), 6.40-6.59 (m, 1H), 4.29 (s, 2H), 4.07 (s, 3H), 3.53 (s, 3H) 2.65 (s, 3H); MS (ESI) 619.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:18])[CH:14](Br)[CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:18])[CH:14]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:15][CH3:16]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(Cl)cc1C=O)C(=O)OC
Temperature: 130 °C
Yield: 93.5 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (156 g, 1 mol), 2-bromo-butyric acid methyl ester (271 g, 1.5 mol), KI (2 g, 0.012 mol) and K2CO3 (276 g, 2 mol) in DMF (500 mL) was heated at 130° C. for 2 h. After cooled to room temperature, the mixture was concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (240 g).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13](Br)[N:12]=2)=[O:10])[NH:6][N:7]=1.NC1C(C(O)=O)=NC([Cl:36])=C(C(F)(F)F)N=1.N1NC(N)=CC=1>>[N:7]1[NH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Cl:36])[N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Reactant: Nc1nc(C(F)(F)F)c(Cl)nc1C(=O)O
Agent: Nc1ccn[nH]1
Product: Nc1nc(C(F)(F)F)c(Cl)nc1C(=O)Nc1ccn[nH]1

Procedure:
The title compound was prepared analogously to 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide Example 1) using 3-amino-6-chloro-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 7) and 2H-pyrazol-3-ylamine. The reaction was carried out using microwave radiation at 100° C. for 1 hour.