Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=[O:4].[Cl:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>>[CH3:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][N:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:13]2[Cl:12])[CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1cccc(C(=O)CBr)n1
Product: Cc1cccc(C(=O)Cn2c(Cl)nc3ccccc32)n1
Yield: 55.2 %

Procedure:
In a manner analogous to Example 28 steps a)→d) 2-bromoacetyl-6-methylpyridine (11.4 g) was reacted with 2-chlorobenzimidazole (8.2 g) to give 1-[2-(6-methylpyrid-2-yl)-2-oxoethyl]-2-chlorobenzimidazole (8.4 g). This wasreacted with thiourea, then NH4OH to give 1-[2-(6methylpyrid-2-yl)-2-oxoethyl]-2-mercaptobenzimidazole (6.9 g); which compound was reduced with NaBH4 to give 1-[2-hydroxy-2-(6-methylpyrid-2-yl]-2-mercaptobenzimidazole (5.0 g.) Treatment of this with polyphosphoric acid gave the title compound (2.1 g.) m.p. 79°-81° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]=[C:16]=[O:17]>C1(C)C=CC=CC=1>[CH3:14][NH:15][C:16]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:17]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)N(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
0.5 moles of diphenylamine was taken in 150 ml of toluene. 0.53 mole of methyl isocyanate and 1 g of acid compound (see Table 1) were added. The mixture was heated at 100° C. for 8 hours, with stirring, and allowed to cool to room temperature, and the N-methyl-N', N'-dipenylurea formed was filtered off. The urea was washed with 100 ml of cold toluene. For the yield, see Table 1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:17][C:16]=1[CH3:36])(=O)=O>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]#[C:21][C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)=[C:16]([CH3:36])[CH:17]=3)=[N:24][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CC1CCNCC1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1CCOS(C)(=O)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1CCN1CCC(C)CC1
Temperature: 69 °C

Procedure:
0.09 mL (0.77 mmol) of 4-methylpiperidine was added to a solution of 110 mg (0.26 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenyl}ethyl methanesulfonate in 2 mL of DMF and heated to 69° C. After the reaction had ended, the reaction solution was cooled and the precipitate formed was suction filtered. Yield: 40 mg (36% of theoretical); C28H29ClN2 (M=428.996) C28H29ClN2; calc.: molpeak (M+H)+:429/431 (Cl); found: molpeak (M+H)+:429/431 (Cl); HPLC-MS: 5.96 minutes (method G).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CN(C)C=O.C[Si]([C:18]#[CH:19])(C)C.CN(C)C(N(C)C)=N>Cl[Cu].Cl[Pd]Cl.O>[NH2:5][C:4]1[CH:3]=[C:2]([C:18]#[CH:19])[CH:8]=[CH:7][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cccc(Br)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cccc(N)c1
Temperature: 45 °C

Procedure:
A 250 ml round bottomed flask, fitted with refrigerator, under a nitrogen stream, is loaded with 3-bromoaniline (2 ml), dimethylformamide (10 ml), trimethylsilylacetylene (3.4 ml), 1,1,3,3-tetramethyl guanidine (2.5 ml), CuCl (3.6 mg), PdCl2 (9.7 mg) triphenyl phosphine (58 mg), in this order. The mixture is heated to 55°-57° C. keeping this temperature until completion of the reaction. H2O (50 ml) and ACOEt (50 ml) are added at a temperature of 35°-30° C. The organic phase is evaporated to dryness and the residue is dissolved in CH3OH (10 ml) and 50% HCl (10 ml) is heated to 40-50° C. for two hours. Methanol is evaporated off and the residual mixture is treated with NaOH, extracted with toluene. The organic phase is dried, and the solvent removed under vacuum affording 3-amino-phenyl acetylene.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:7]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:6]2[CH:29]=1)#[N:2].[N-:30]=[N+:31]=[N-:32].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:7]1[N:6]2[CH:29]=[C:3]([C:1]3[NH:32][N:31]=[N:30][N:2]=3)[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2nc(C#N)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2nc(-c3nnn[nH]3)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 70.1 %

Procedure:
To a stirred solution of tert-butyl (2-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 152, 27 mg, 0.06 mmol) in DMF (2 mL) was added NaN3 (6 mg, 0.09 mmol) and NH4Cl (5 mg, 0.09 mmol). After heating to 100° C. for 24 h, the reaction was diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded crude tert-butyl (5-(2,4-dichlorophenyl)-7-methyl-2-(1H-tetrazol-5-yl)imidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (20 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([NH:35]O)=[NH:34])=[CH:31][N:30]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:35]=[C:33]([C:32]5[CH:37]=[CH:38][C:29]([NH2:28])=[N:30][CH:31]=5)[N:34]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (98 mg, 39%). MS (ISP) 506.2 [(M+H)+]; mp 220° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:8].[CH3:29][O:30][C:31]1[CH:67]=[CH:66][C:34]([CH2:35][N:36]2[CH:40]([CH2:41][CH2:42]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:39][N:38]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)[C:37]2=[O:65])=[CH:33][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:42][CH2:41][CH:40]2[CH2:39][N:38]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:60]=3)[C:37](=[O:65])[N:36]2[CH2:35][C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:67][CH:66]=2)=[CH:15][CH:14]=1)[CH3:8]
Reactant: COc1ccc(CN2C(=O)N(Cc3ccc(C(F)(F)F)cc3)CC2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Yield: 93.6 %

Procedure:
Cesium carbonate (2.49 g, 7.647 mmol) is added to a solution of 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.77 g, 5.88 mmol) and toluene-4-sulfonic acid 2-[3-(4-methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (3.64 g, 6.47 mmol) in DMF (40 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, then dried, concentrated, and purified by flash chromatography (acetone/hexanes gradient) to provide the title compound (3.80 g, 94%). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=7.8 Hz), 7.23-7.19 (m, 4H), 7.13 (d, 2H, J=8.4 Hz), 6.97 (t, 1H, J=7.8 Hz), 6.86 (d, 2H, J=8.4 Hz), 6.81 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=7.8 Hz), 4.66, 4.20 (ABq, 2H, J=14.9 Hz), 4.47, 4.43 (ABq, 2H, J=15.5 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.89-3.85 (m, 2H), 3.80 (s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 1H, J=9.1 Hz), 3.26, 3.08 (ABq, 2H, J=13.6 Hz), 3.00 (t, 1H, J=9.1 Hz), 2.20-2.14 (m, 1H), 1.87-1.78 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 691 (M+H)+. Rf=0.46 in 50% acetone in hexanes.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.Cl.[CH3:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH2:20].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[F:8][C:7]1[CH:6]=[N:5][C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]=1[NH:20][C@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH3:13]
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: C[C@@H]1CCCC[C@@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCCC[C@@H]1Nc1c(F)cnc2[nH]ccc12
Temperature: 200 °C
Yield: 34.5 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (60 mg), (1S,2R)-2-methylcyclohexanamine hydrochloride (105 mg) and N,N-diisopropylethylamine (123 μL) in NMP (0.3 mL) was heated in the microwave reactor (200° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. Purification of the product by column chromatography (silica gel, gradient elution, 1:1 EtOAc/n-hexane to EtOAc) provided 5-fluoro-N-[(1S,2R)-2-methylcyclohexyl]-1H-pyrrolo[2,3-b]pyridin-4-amine (30 mg) as a tan solid.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+]>Cl>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:2][CH:1]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)N1CC(O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1ccc(N)cc1
Temperature: 140 °C

Procedure:
A mixture of 21.8 g of p-aminophenol, 22 g of 1-(tert.-butyl)-3-azetidinol and 0.73 g of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and dissolved in concentrated hydrochloric acid and the solution was extracted with ether. The hydrochloric acid aqueous solution was made alkaline with 10% -NaOH aqueous solution and then extracted with ether. The ether solution was washed with water and dried over anhydrous sodium sulfate. Then ether was distilled off and the residue was recrystallized from benzene. As a result 8g of 1-(p-aminophenoxy)-3-(tert.-butylamino)-2-propanol melting at 125° - 127° C were obtained. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis are as follows:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.CN(C=O)C.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CCOC(C)=O>[N:22]1([C:2]2[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.397 mmol) in pyrrolidine (1.0 ml) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 91%).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][NH:4]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:28][C:25]([F:26])([F:27])[C:24]([C:21]1[CH:22]=[N:23][C:18]([N:4]2[CH2:5][CH2:6][N:7]([S:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)(=[O:11])=[O:10])[CH2:8][C@@H:3]2[CH3:2])=[N:19][CH:20]=1)([OH:33])[C:29]([F:32])([F:31])[F:30]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 85 °C

Procedure:
A 20-mL vial was charged with (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (0.75 g, 2.6 mmol, Example 27), (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.92 g, 3.3 mmol, Intermediate D), 15 mL of dioxane, and Hünig's base (1.2 mL, 6.6 mmol). The mixture was heated at 85° C. for 12 h and then concentrated and purified via column chromatography on silica gel (0 to 50% EtOAc in hexanes) delivered 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.360 g). 1H NMR (400 MHz, CD3OD) δ=8.58 (s, 2H), 7.87 (d, J=5.1 Hz, 1H), 7.66-7.63 (m, 1H), 7.28-7.23 (m, 1H), 5.14 (br. s., 1H), 4.76 (d, J=13.9 Hz, 1H), 3.83 (d, J=11.3 Hz, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.40 (s, 1H), 2.69-2.58 (m, 1H), 2.47 (dt, J=3.6, 12.0 Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 491.0 (M+H)+. GK-GKRP IC50 (Binding)=0.362 μM; GK-GKRP EC50 (LC MS/MS-2)=0.470 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)[CH:10]=1.CS(O)(=O)=O.C([SiH](CC)CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(Cc2ccc(F)cc2)c1

Procedure:
To a stirred solution of 2-(3-chloro-4-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-5-methyl-phenyl)-2H-[1,2,4]triazine-3,5-dione (0.4 g) in dichloromethane (25 mL) were added methanesulfonic acid (0.7 mL) and triethylsilane (1.5 mL) portionwise over 1 h. After a total of 1.5 h, water was added, the layers separated and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (10-50% THF/hexanes) to afford the title compound of this EXAMPLE as a colorless foam, 56 mg. MS Calc.:453.9; Found:452.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].N1CCCCC1.[Br-:13].[NH2:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[Br-:13].[Cl:1][CH2:2][CH2:3][C:4]([NH:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C(CCCl)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
3-Chioropropionyl chloride (3.0 ml, 32 mmol) and piperidine (3.5 ml, 43.5 mmol) were added to a suspension of 2-aminobenzyltriphenylphosphonium bromide (13.0 g, 29 mmol) (synthesised using the procedure of Capuano et al, Chem. Ber., 1986, 119, 2069-2074) in dichloromethane (60 ml) under a nitrogen atmosphere. The mixture was heated at reflux for 30 min. and then cooled to room temperature. Dichloromethane (60 ml) and hydrochloric acid (1N, 50 ml) were added and the precipitated solid was collected by filtration, washed with dichloromethane and dried in vacuo to give 2-(3-chloropropionylamino)benzyltriphenylphosphonium bromide (7.5 g, 48%). The filtrate was diluted with dichloromethane (300 ml) and washed with sodium carbonate (satd., 150 ml). Evaporation of the dichloromethane gave a residue which was triturated with ether (200 ml) and the white solid collected to afford a second crop of product (5.0 g, 32%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][N:16]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[N:15]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CN(C=O)C.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][N:16]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:20]4)[N:15]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)n3)n2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(CC(F)(F)F)C4)n3)n2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
2-(3-(3-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 130; 13.0 mg, 0.0301 mmol) was suspended in DMF (301 μL, 0.0301 mmol) and treated with diisopropylethylamine (31.4 μL, 0.180 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.07 mg, 0.0391 mmol). The reaction mixture was stirred at ambient temperature for 15 hours. Another portion of 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.0 mg, 0.87 mmol) was added and stirred for another 24 hours. The reaction mixture was then purified by reverse phase HPLC using 0-100% acetonitrile/water gradient, followed by preparative TLC using 10% MeOH/EtOAc to afford 2-(3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (9.6 mg, 72% yield). MS (apci) m/z=442.3 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][NH:13][CH3:14])[CH3:2].[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:20][C:19]=2[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][N:13]([CH3:14])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1)[CH3:2]
Reactant: CCc1c(CNC)oc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of (3-ethylbenzofuran-2-yl)-N-methylmethanamine (89 mg, 0.49 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (111 mg, 0.44 mmol), 1-hydroxybenzotriazole (68 mg, 0.49 mmol), diisopropylethylamine (232 uL, 1.34 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (98 mg, 0.49 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield title compound as a pale brown solid (134 mg, 70%): 1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.18-7.64 (m, 5H), 4.81-5.01 (rotamers, 2s, 2H), 3.27-3.61 (m, 2H), 2.90 (d, J=9.0 Hz, 2H), 2.73-2.78 (m, 2H), 2.51-2.59 (m, 3H), 1.23 (t, J=9.0 Hz, 3H); MS (ESI) m/e 390 (C23H23N3O3+H)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[C:25](Cl)=[C:26]([C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:27]([CH3:31])=[N:28][C:29]=1[CH3:30]>CC#N.CCOCC>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:25]2[C:24]([Br:23])=[C:29]([CH3:30])[N:28]=[C:27]([CH3:31])[C:26]=2[C:32](=[O:39])[C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
To a solution of 4-benzylpiperidine (0.80 g, 4.56 mmol) and DIEA (2.4 mL, 13.7 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.7 g, 4.56 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 18 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (0-25% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.48 g (68%). 1H NMR (500 MHz, DMSO-d6) δ 7.3-7.27 (m, 2H), 7.20-7.15 (m, 3H), 5.09-5.04 (m, 1H), 3.23 (br. s, 2H), 2.84 (br. s, 2H), 2.59 (s, 3H), 2.51-2.49 (m, 2H), 2.28 (s, 3H), 1.61 (br. s, 1), 1.55 (d, J=13.6 Hz, 2H), 1.30 (d, J=6.2 Hz, 6H), 1.14 (br. s, 2H). UPLC (M+H)=475.2.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH3:12]>C(O)C>[NH2:12][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1cc(F)cc(F)c1F
Solvent: CCO
Product: N#Cc1cc(F)cc(F)c1N
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of 2,3,5-trifluorobenzonitrile (25.0 g, 159 mmol) and ethanol (300 ml) pre-saturated with ammonia gas was heated at 120° C. in an autoclave for 8 h. The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was partitioned between water (1 l) and ethyl acetate (1 l). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2) to afford 3.7 g (15%) of the title compound as a cream solid: 1H NMR (360 MHz, CDCl3) δ 4.08 (2H, s), 6.60-6.64 (1H, m), 6.67-6.72 (1H, m).