Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH:17]([NH2:20])=[CH:18][CH3:19]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:11])[CH2:7]1
Reactant: CC=CN
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
A stirred solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 3.0 g (0.04 mole) of propenylamine, and stirring was continued for 18 hr. The reaction mixture was diluted with 200 ml of ice water, and the solid which formed was collected by filtration, yielding 7.1 g of crude wet product. Recrystallization from benzene/ligroin yielded 3.95 g (65.6%) of white crystals, m.p. 98°-99° C.
Reaction SMILES: C([O:5][C:6](=O)[C@H:7]([O:10][C:11]1[CH:34]=[CH:33][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:25]=[CH:26][N:27]=1)[N:16]=3)[CH2:8][CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[CH2:28][N:24]1[C:23]([C:17]2[N:16]=[C:15]3[C:14]4[CH:33]=[CH:34][C:11]([O:10][C@H:7]([CH2:8][CH3:9])[C:6]([NH2:44])=[O:5])=[CH:12][C:13]=4[O:22][CH2:21][CH2:20][N:19]3[CH:18]=2)=[N:27][CH:26]=[N:25]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of (R)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester in DCM (3 mL) was added TFA (0.5 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU (217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 495 as a white solid (60 mg, 48%). LCMS: RT=3.78 min, [M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.50 (1H, br s), 7.24 (1H, br s), 6.74 (1H, dd, J=8.9, 2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.52-4.39 (5H, m), 1.79 (2H, pent, J=7.2 Hz), 0.92 (3H, t, J=7.2 Hz)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[Cl:11][C:12]1[N:17]=[C:16]2[C:18]([CH:21]=O)=[CH:19][S:20][C:15]2=[CH:14][CH:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]2[C:18]([CH2:21][NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])=[CH:19][S:20][C:15]2=[CH:14][CH:13]=1
Reactant: CCOC(OCC)[C@H](C)N
Reactant: O=Cc1csc2ccc(Cl)nc12
Product: CCOC(OCC)[C@H](C)NCc1csc2ccc(Cl)nc12
Yield: 30.3 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-6, (S)-1,1-diethoxypropan-2-amine (Compound XVIII-1) (1.98 g, 13.4 mmol) was reacted with 5-chlorothieno[3,2-b]pyridine-3-carbaldehyde (Compound XIX-1) (1.98 g, 10 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=98:2 to 95:5) to obtain the title compound (996 mg, 30%).
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[C:14]1(=[O:28])[N:18]([CH2:19][C:20](=O)[CH3:21])[C:17](=[O:23])[C:16]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:15]12.O>CN(C)C=O>[O:23]=[C:17]1[C:16]2[C:15](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14](=[O:28])[N:18]1[CH2:19][C:20]([CH3:21])=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=C(C)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 80.7 %

Procedure:
A solution of methyl dimethylphosphonoacetate (21.5 g) in N,N-dimethylformamide (50 mL) was added dropwise to a suspension of sodium hydride (63%, 4.50 g) in N,N-dimethylformamide (100 mL) with stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, a solution of phthalimidoacetone (20.0 g) in N,N-dimethylformamide (50 mL) was added dropwise thereto, and the mixture was heated to room temperature and stirred overnight. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (20.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[N:46][CH:45]=[C:44]([S:48]([N:51]6[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]6)(=[O:50])=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(S(=O)(=O)c2cncc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cncc(S(=O)(=O)N4CCN(C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-(5-bromo-pyridine-3-sulfonyl)-4-methyl-piperazine (prepared from 5-bromo-pyridine-3-sulfonyl chloride and N-methylpiperazine, 65 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-07, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[5-(4-methyl-piperazine-1-sulfonyl)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-249) as a milky white powder (66 mg, 66%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:11]([CH3:23])[CH:10]=2)[C:3]=1[NH2:24].[I-:25].[Na+].O.C(=O)([O-])O.[Na+]>I.C(OCC)(=O)C>[IH:25].[I:25][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:11]([CH3:23])[CH:10]=2)[C:3]=1[NH2:24]
Reactant: [I-]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(Cl)c3N)cc2C)cn1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Temperature: 70 °C
Yield: 95.3 %

Procedure:
6-Chloro-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine (400 mg) was suspended in 55% hydriodic acid (6.16 mL), sodium iodide (878 mg) was added, and the mixture was stirred with heating at 70° C. for 10 min. After cooling to room temperature, water (40 mL)/ethyl acetate (30 mL) was added. After adjusting its pH to not less than 7 with aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (626 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].Br[CH2:17][CH2:18][CH:19]([Br:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([CH2:17][CH2:18][CH:19]([Br:21])[CH3:20])[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CC(Br)CCBr
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1N(CCC(C)Br)S(C)(=O)=O
Reaction time: 1 h
Yield: 65.6 %

Procedure:
15.5 g (0.517 moles) of a 80% sodium hydride dispersion, containing 20% of mineral oil, are added in small portions, within 0.5 hours, to a suspension of 100 g (0.5 moles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 800 ml of dry xylene at room temperature, and the mixture is heated then to 130° C. within one hour. 102.5 ml (184.5 g, 0.85 moles) of 1,3-dibromo-butane are added dropwise, within 3 hours, to the mixture at 130°-135° C., and the mixture is stirred at the same temperature for additional 4 hours. Thereafter the mixture is cooled, washed twice with 200 ml of water, twice with 250 ml of 1 n aqueous sodium hydroxide solution, once with 200 ml of water, twice with 200 ml of 1 n aqueous hydrochloric acid solution and finally twice with 200 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 109.65 g (66%) of crude 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-3-bromo-butane are obtained as a dark yellow oil; this substance can be utilized in the next step without purification.
Reaction SMILES: [N:1]1([C@@H:6]([CH2:11][C:12](OC)=[O:13])[C:7](OC)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li+].[BH4-]>C1COCC1>[N:1]1([C@@H:6]([CH2:11][CH2:12][OH:13])[CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COC(=O)C[C@@H](C(=O)OC)n1cccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC[C@@H](CO)n1cccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
In a two necked flask cooled in an ice bath and under argon atmosphere, dimethyl(2S)-2-(1H-pyrrol-1-yl)butanedioate (19 mmol, 4.0 g) was dissolved in 10 ml of dry THF. LiBH4 (57 mmol 1.14 g) was added portionwise and the reaction was stirred for 6 hours at 0° C. When the reaction was completed, it was quenched by addition of 2M HCl and Ethyl Acetate (30 ml). The aqueous layer was extracted with ethyl acetate 2 times and the combined organic layers were dried, filtered and evaporated. The crude residue was purified by chromatography on silica gel (eluent: DCM/MeOH:95/5) to give the product as a colourless oil (2.8 g, 95% yield, e.e. %=97.5).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].S(O)(C)(=O)=O.C1C(=O)N([Br:23])C(=O)C1>>[Br:23][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1C#N
Agent: CS(=O)(=O)O
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 50 °C
Reaction time: 33 h

Procedure:
To a 3 L 3 Neck round bottomed flask equipped with overhead stirrer was charged 2-Fluoro-6-methyl-benzonitrile (191.8 g., 1419 mmol) and MsOH (563 mL, 8516 mmol). NBS (265 g., 1490 mmol) was added portionwise to this stirred solution over 30 minutes, and the mixture was stirred at 50° C. for 33 hours. By that time, HPLC showed the reaction to be mostly complete, so the reaction was poured into 1 L of ice (exotherm noted), diluted with 700 mL 30% EtOAc/Hexanes, and agitated. The aqueous layer was cut, and the organics washed 2× with 1N NaOH and with water. The aqueous cuts were observed to be significantly enriched with impurities. The organics were dried over MgSO4, concentrated, then stored in a −10° C. freezer overnight. Precipitate formed over this time, and was filtered and washed with 5% EtOAc/Hexanes, providing a first crop of product. A second crop of precipitate provided further 3-Bromo-6-fluoro-2-methyl-benzonitrile.
Reaction SMILES: O1CCC[CH2:2]1.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O.C(OCC)(=O)C>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:2])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3ncc(Cl)cc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1Cc2ncc(Cl)cc2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (195 ml) of tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (13.0 g) was added dropwise at −78° C. a tetrahydrofuran solution (1 M, 39.1 ml) of lithium hexamethyldisilazide. After stirring at the same temperature for 30 minutes, a tetrahydrofuran solution (65 ml) of methyl iodide (2.65 ml) was added dropwise. After stirring at the same temperature for 10 minutes and under ice cooling for 1 hour, ethyl acetate and water were added to the reaction solution, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-3-methyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (12.2 g).
Reaction SMILES: O[C:2]1[C:3]2[S:14][CH2:13][CH2:12][CH2:11][C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:3]2[S:14][CH2:13][CH2:12][CH2:11][C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=1
Reactant: COCc1nc(O)c2c(n1)CCCS2
Reactant: O=P(Cl)(Cl)Cl
Product: COCc1nc(Cl)c2c(n1)CCCS2

Procedure:
The title compound was prepared following substantially the same procedure described in Example 1, step B using the product from step B of this Example 3 and phosphorus oxychloride. This procedure gave 1.0 g of title compound which was dried and used in step D without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:34].FC(F)(F)S(O)(=O)=O>ClCCl>[I:34][C:9]1[C:5]2[NH:6][C:7](=[O:8])[C:2]([CH3:16])([CH3:1])[O:3][C:4]=2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: [IH2+]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(I)c2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a suspension of 2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 1(1), 1.00 g) in dichloromethane (50 mL) was added bis(pyridine)iodonium tetrafluoroborate (1.68 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were further added bis(pyridine)-iodonium tetrafluoroborate (0.84 g) and trifluoromethanesulfonic acid (1.2 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. The resultant residue was diluted with ethyl acetate, tetrahydrofuran and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous saturated sodium hydrogencarbonate solution, an aqueous 15% sodium thiosulfate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was triturated in n-hexane/ethyl acetate to give 5-iodo-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (0.90 g) as a pale brown powder.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:37]2[N:44]=[C:45]([C:47]([OH:49])=O)[CH:46]=[C:36]2[N:35]=1.[CH2:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:50]([NH:57][C:47]([C:45]1[CH:46]=[C:36]2[N:35]=[C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[N:37]2[N:44]=1)=[O:49])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc2nc(-c3ccccn3)cc(C(F)(F)F)n2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCc1ccccc1)c1cc2nc(-c3ccccn3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.430 g, 0.973 mmol) was added to a suspension of 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.250 g, 0.811 mmol) and benzylamine (0.106 mL, 0.973 mmol) in tetrahydrofuran (10 mL) containing triethylamine (0.339 ml, 2.43 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (10 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and crude the product was purified by column chromatography on silica gel to give 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid benzylamide (0.280 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[F:23])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2ccccc2F)cc1

Procedure:
To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediamine (1.58 g) and triethylamine (1.50 mL) in 25 mL of dichloromethane is added o-fluorobenzoyl chloride (1.20 g). A solid formed immediately forms and is filtered and washed with fresh solvent to yield a white solid, 1.90 g.
Reaction SMILES: [C:1](=[S:3])=S.[F:4][C:5]([F:15])([F:14])[C:6]1[C:7]([NH:12][NH2:13])=[N:8][CH:9]=[CH:10][CH:11]=1>N1C=CC=CC=1>[SH:3][C:1]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:5]([F:15])([F:14])[F:4])[C:7]2=[N:12][N:13]=1
Reactant: S=C=S
Reactant: NNc1ncccc1C(F)(F)F
Solvent: c1ccncc1
Product: FC(F)(F)c1cccn2c(S)nnc12
Reaction time: 0.25 h

Procedure:
16 ml of carbon disulfide are added dropwise at room temperature, with stirring, to a suspension of 40 g of 3-trifluoromethyl-2-hydrazinopyridine, prepared in Example 12, in 75 ml of pyridine. When the additioon is complete, stirring is continued for 15 minutes at room temperature and the reaction mixture is then heated under reflux for 5 hours. After cooling, the medium is concentrated in vacuo and water is then added. The solid residue obtained is filtered off, washed with water and dried to give 40 g of 3-mercapto-8-trifluoromethyl-1,2,4-triazolo(4,3-a)pyridine in the form of crystals melting at 236° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.C([C:22]1[C:23]([N:31]=[CH:32][N:33]([CH3:35])C)=[N:24][C:25]([CH:28]2[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:28]1([C:25]2[CH:26]=[CH:27][C:22]3[C:35]([NH:1][C:2]4[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=4[S:9][C:10]4[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=4)=[N:33][CH:32]=[N:31][C:23]=3[N:24]=2)[CH2:29][CH2:30]1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ncnc3nc(C4CC4)ccc23)cc1

Procedure:
The product from Example 7b was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 7b for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.13 (d, J=6.25 Hz, 4H), 2.02 (s, 3H), 2.22-2.38 (m, 1H), 2.31 (s, 3H), 7.07 (s, 2H), 7.20 (d, J=8.82 Hz, 2H), 7.30 (s, 1H), 7.50 (d, J=8.82 Hz, 2H), 7.56 (d, J=8.46 Hz, 1H), 8.49 (s, 1H), 8.68 (d, J=8.82 Hz, 1H), 9.99 (s, 2H); MS (ESI+) m/z 442 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:12]4[N:11]=[CH:10][N:9]=[C:8]5[C:13]=4[N:14]=[CH:15][N:7]5[CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:18][CH:19]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3ncn4C3CCCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of 4-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yloxy]-phenylamine (0.311 g, 1 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.334 g, 1.5 mmol) in DMF (5 mL) was added TEA (216 μL, 2 mmol) followed by HATU (0.76 g, 2 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water (25 mL) and extracted with EtOAc (2×). The combined organic extracts were washed with 10% LiCl(aq.) (4×), satd. NaHCO3(aq) (2×), water, (1×) and brine (1×), followed by drying over MgSO4 and concentration in vacuo. The crude solids were purified by flash chromatography (silica gel, 1:1 EtOAc:Hexanes containing 2% 7N NH3 in MeOH), affording N-(4-fluorophenyl)-N′-(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide (0.430 g, 83% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 8.95 (s, 1H), 8.45 (s, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 7.20 (m, 2H), 7.0 (m, 2H), 5.8 (m, 1H), 4.20 (m, 1H), 3.8 (m, 1H), 2.20 (m, 3H), 1.80 (m, 2H), 1.7 (m, 5H). MS (ESI) for C27H25FN6O4: 517 (MH+).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:38])[CH2:22][NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[O:38]=[C:21]([N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[CH2:22][NH:23][C:24]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 94.8 %

Procedure:
TFA (3.6 mL) was added to a stirred solution of 4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carboxylicacid tert-butyl ester (1.7 g, 4.01 mmol) in DCM (18 mL) at 0-4° C. and the resulting mixture was stirred at this temperature for 3 hrs. The reaction mixture was concentrated to afford 1.67 g (94.8% yield) of biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt. LC-MS purity: 85.4%,