Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CN(C=O)C.C(Cl)(Cl)Cl>[NH:1]([C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCCCBr
Reactant: Clc1nc(Nc2ccccc2)nc2nc[nH]c12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCCn1cnc2c(Cl)nc(Nc3ccccc3)nc21
Yield: 45 %

Procedure:
Reaction between 2-anilino-6-chloropurine and 4-acetoxybutyl bromide was performed as described in A.a., above, giving 2-anilino-6-chloro-9-(4-acetoxybutyl) purine in a 45% yield (from DMF/chloroform), mp 195°-197° C. 1H NMR δ9.98 (s, 2-NH), 8.32 (s, 8-H), 7.31 (m, C6H5), 4.20 (t, 1'-CH2), 4.02 (t, 4'-CH2), 1.95 (s, CH3), 1.92, 1.58 (m, 2'/3'CH2).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[CH:13]1([CH2:18][CH2:19][CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:18][CH2:19][CH2:20][O:21][NH2:2])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCCCC1CCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCCCC1CCCC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and 3-cyclopentyl-1-propanol (Aldrich). 13C-NMR (CDCl3) δ 76.5, 40.0, 32.7, 32.4, 27.7, 25.2.
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[C:8](=[O:27])[N:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=3)[C:10]3[N:11]([CH:14]=[CH:15][N:16]=3)[C:12]=2[N:13]=1)=O.[NH2:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]3([CH2:47][CH2:46]3)[CH2:34][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)=[CH:31][CH:30]=1>C(#N)C.C(OCC)(=O)C>[O:27]=[C:8]1[C:7]2[CH:6]=[N:5][C:4]([NH:28][C:29]3[CH:38]=[C:37]4[C:32]([C:33]5([CH2:46][CH2:47]5)[CH2:34][N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:36]4)=[CH:31][CH:30]=3)=[N:13][C:12]=2[N:11]2[CH:14]=[CH:15][N:16]=[C:10]2[N:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=1
Reactant: C=CCOc1ccc(-n2c(=O)c3cnc(S(C)=O)nc3n3ccnc23)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C2(CC2)C1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(-n2c(=O)c3cnc(Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC54CC4)nc3n3ccnc23)cc1
Temperature: 60 °C

Procedure:
To a solution of Example 205E (125 mg, 0.328 mmol) in 4 mL acetonitrile was added tert-butyl 7′-amino-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-carboxylate (108 mg, 0.393 mmol). The reaction was heated to 60° C. overnight, cooled, diluted with ethyl acetate, washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by chromatography with an Analogix 280 with an SF 24-40 column, 20% to 100% ethyl acetate/hexane gradient over 30 minutes to provide the title compound. MS (ESI+) m/z 592.36 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1cccc(C2CCNCC2)c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 30% overall yield. mp 121°-123°. FDMS m/e=381 (M+ of free base). α[D]589 =-12.69 (c=0.53, methanol).
Reaction SMILES: N(OC(C)(C)C)=[O:2].N[CH:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]1=[O:26].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:24]([O:23][C:21]([CH2:20][N:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][C:9](=[O:2])[C:10]1=[O:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: CC(C)(C)ON=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Temperature: 25 °C

Procedure:
t-Butyl nitrite (31 ml) was added with stirring to a solution of 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2-one (55 g) in chloroform (1000 ml) and acetic acid (2.8 ml). The reaction mixture was refluxed under nitrogen for 3.5 hours, and then cooled to 0°. While stirring was maintained, m-chloroperbenzoic acid (43.5 g) was added in five portions during 0.5 hour. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1.5 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (500 ml), concentrated aqueous ammonia (2×250 ml), and saturated brine (250 ml). The organic solution was dried over sodium sulfate, treated with charcoal, and evaporated under reduced pressure to give an oil which was triturated with ether to give 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2,3-dione, m.p. 112°-114°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:25]>O1CCOCC1>[NH2:25][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)ccc1-c1cnco1
Reactant: N
Solvent: C1COCCO1
Product: COc1cc(NC(=O)c2c(N)ncnc2Cl)ccc1-c1cnco1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
4,6-Dichloro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)pyrimidine-5-carboxamide (844 mg, 2.01 mmol) was dissolved in dioxane (10 ml) and cooled in an ice bath. Ammonia solution (1.44 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 20 min and 4 h at room temperature. After dilution with ethyl acetate, this organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield a solid as a residue (788 mg, 86% purity, 98% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][C:2]1([CH3:1])[C:3]([CH3:17])([CH3:16])[O:4][B:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:43]3[CH2:47][CH2:46][CH2:45][C@H:44]3[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:13])=[CH:14][CH:15]=2)[O:6]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.00 g, 8.06 mmol) in DMF (20 mL) was added HATU (6.20 g, 16.3 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate (2.00 g, 11.7 mmol) and DIPEA (4.20 g, 32.5 mmol). The reaction mixture was stirred at rt overnight, and was quenched with H2O (20 mL). The resulting solution was extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:20-1:10 v/v) to obtain compound 17a as a yellow solid (1.40 g, 37% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H32BNO5: 402.2 (M+H). Found 402.1.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[Br:15][C:16]1[CH:21]=[N:20][C:19]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+].NN1C=CN=CC1>C(Cl)Cl.CN(C=O)C>[Br:15][C:16]1[N:17]=[CH:18][C:19]2[N:20]([N:13]=[C:23]([Si:24]([CH3:26])([CH3:25])[CH3:27])[CH:22]=2)[CH:21]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)cn1
Agent: NN1C=CN=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[Si](C)(C)c1cc2cnc(Br)cn2n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
O-(Mesitylenesulfonyl)hydroxylamine (680 mg, 3.2 mmol) was added in one portion to a stirred solution of 2-bromo-5-trimethylsilanylethynyl-pyrazine (Step 1, 3 mmol) in CH2Cl2 (3 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, at RT for 4 hours, then evaporated. The N-amino adduct was used without further manipulation. K2CO3 (410 mg, 3 mmol) was added to a stirred solution of the N-aminopyrazine from above in dry DMF (5 ml) at RT under nitrogen. After 6 hours the mixture was partitioned between EtOAc/H2O. The organic layer was washed with brine (×2), then evaporated. The residue was taken up in CH2Cl2 and passed through a phase separating cartridge. The filtrate was evaporated and the residue was purified by chromatography on silica (2→4% EtOAc/Petrol) to give the title compound (62 mg, oil) MS: [M+H]+ 270/272.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[Cl-].[NH4+].CC([N:38](C)C)=O.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH2:38])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:23])([F:25])[F:24])[O:11][N:10]=1
Reactant: CC(=O)N(C)C
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Saponification of the ester of example 11 was achieved following the description for example 19, first step, to give 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid in 89% yield. To a solution of 6.0 g (12.34 mmol) 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid and 1.98 g (37.021 mmol) ammoniumchlorid in 20 mL dry DMA 9.36 g (24.681 mmol) HBTU and 6.45 mL (37.021 mmol) DIPEA were added. The mixture was stirred 3 hours at r.t. Ethylacetate was added to the reaction mixture and it was washed twice with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in the vacuum. The oily residue became solid by drying in the vacuum. The solid was washed with petroleum ether, filtrated and dried in the vacuum to yield 5.37 g (90%) of example 121. Result of LC/MS MH+: 484.83; 1H NMR (DMSO-d6; CCl4): 7.39-7.78 (7H, m, CH-arom./2H NH2), 8.43 (1H, s, CH-pyraz.)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:27]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)=[O:34])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccncc1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 8 h

Procedure:
To a mixture of 0.45 g (1.75 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.707 g (6.99 mmol) of triethylamine and 5 ml of dimethylformamide at ice-water bath temperature is added dropwise a solution of 0.247 g (1.75 mmol) of isonicotinoyl chloride hydrochloride and 1 ml of dimethylformamide. The reaction mixture is allowed to stir overnight while slowly reaching room temperature. A white precipitate is formed which is collected by filtration, washed with water and dried to yield 0.320 (50%) of the title compound as a white solid: m.p.>250° C.; m/e 362.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38]>CN(C=O)C.O>[NH2:39][C:37](=[O:38])[CH2:36][N:20]1[C:21]2[C:17](=[CH:16][C:15]([NH:14][C:12]([C:8]3[CH:7]=[C:6]([N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:24][CH2:25][CH3:26])[N:11]=[CH:10][N:9]=3)=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(N)=O)c2)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), potassium iodide (1 mg) and 2-bromoacetamide (160 mg; 1.16 mmol). After stirring at RT for 72 hours the mixture was poured in water (20 ml) and stirred at RT for 1 hour. The solid was removed by filtration, washed with water and dried. The residue was purified by column chromatography (silica) eluting with EtOAc containing increasing amounts of MeOH to give the title compound as an off-white solid, together with N-[2-(2-amino-2-oxoethyl)-2H-indazol-5-yl]-6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxamide (Example 118 below).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17].CC[O-].[Na+].O>CCO>[C:1]([NH:4][C:5]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC

Procedure:
Diethyl 2-acetamidomalonate was treated with 4-cyanobenzyl bromide and NaOEt in EtOH, to give after dilution with H2O, and isolation of the resulting precipitate, diethyl 2-acetamido-2-(4-cyanobenzyl)malonate. This product was heated in HCl, and the mixture evaporated to give 4-carboxy-D,L-phenylalanine hydrochloride [D,L-Phe(4-CO2H)-OH.HCl]. This product was treated with MeOH and HCl gas to give after evaporation, D,L-Phe(4CO2Me)-OMeHCl. This product was treated with N-(toluene-4-sulfonyl)-L-Pro-OH, BOP, and NMM in DMF, to give after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-L-Pro-D,L-Phe(4-CO2Me)-OMe. This product was treated with NaOH in dioxane and water, to give after acidification, extraction, drying with MgSO4, filtration and evaporation the title compound as a clear oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O>O1CCCC1>[N:13]1([C:2]2[N:11]=[C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(N3CCCC3)nc(N3CCCC3)nc2c1

Procedure:
Ten grams of 2,4-dichloroquinazoline was added carefully to a solution of 25 ml of pyrrolidine in 200 ml of tetrahydrofuran. The resulting mixture was heated at reflux overnight and then was poured into a mixture of ice and water. The resulting mixture was extracted several times with ether. The ether extracts were combined and washed with water. The ether phase then was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a 1:1 benzene:hexane mixture to give 10.1 g of 2,4-bispyrrolidinylquinazoline; m.p. 127°-129°. The following analytical data were obtained:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:16]=2)=[CH:12][C:11]=1[C:26]1[N:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:27]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:16]=2)=[CH:12][C:11]=1[C:26]1[N:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[N:27]=1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(C=O)ccc3Cl)o2)c(C)cn1
Reactant: C1CCNC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(CN4CCCC4)ccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of N-{4-[5-(2-chloro-5-formylphenyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.19 g, 0.34 mmol) in DCM (10 mL) was added pyrrolidine (0.14 mL, 1.68 mmol) and STAB (0.21 g, 1.01 mmol). The mixture was allowed to stir at rt overnight. The mixture was diluted with water and extracted with DCM. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-{5-[2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.20 g, 100%). LCMS (FA): m/z=607.7 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:24](=[O:25])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][N:21]([CH3:33])[CH:20]=3)=[O:18])=[C:11]([F:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][N:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=3)[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:24](=[O:25])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]([CH3:33])[CH:20]=1)=[O:18]
Reactant: Cn1cc(B(O)O)cn1
Reactant: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(-c4cnn(C)c4)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (0.125 g, 0.221 mmol) was combined with 1-methyl-pyrazole-4-boronic acid (0.058 g, 0.277 mmol) and K2CO3 (0.092 g, 0.664 mmol) in dioxane (2 mL) and H2O (0.333 mL), the mixture sparged with argon, treated with Pd(PPh3)4 (0.013 g, 0.011 mmol), sparged again with argon, and heated to 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, washed with H2O, then brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (103 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.50 (s, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.57 (dd, J=12.7, 7.2 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J=2.3 Hz, 1H), 7.98 (s, 1H), 7.70 (dd, J=8.6, 5.6 Hz, 2H), 7.58 (dd, J=11.0, 7.4 Hz, 1H), 7.30-7.22 (m, 3H), 6.74 (dd, J=5.7, 2.5 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H); MS (ESI) m/z: 532.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: CC(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(C)C)cc2)cc1-c1c(Br)cnn1C
Yield: 50 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-isopropylphenyl isocyanate (0.022 g, 21.0 μL, 10.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 23 (0.028 g, 0.06 mmol, 50%) as a solid film. LCMS m/z (%)=443 (M+H79Br, 100), 445 (M+H81Br, 99). 1H NMR (400 MHz, acetone-d6) δ: 8.08 (s, 1H), 8.00 (s, 1H), 7.68 (dd, J=2.6, 8.9 Hz, 1H), 7.49 (s, 1H), 7.40-7.46 (m, 3H), 7.09-7.17 (m, 3H), 3.81 (s, 3H), 3.68 (s, 3H), 2.78-2.92 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[C:18](Cl)=[N:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18]([O:30][CH3:29])=[N:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:25][CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cn1nc(Cl)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nn(C)c(=O)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c12
Yield: 39 %

Procedure:
The procedure of Example 34 was repeated except that 1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7-chloroimidazo[4,5-d]pyridazin-4(5H)-one was used as the starting compound. Thus, this starting compound (52 mg) was dissolved in methanol (5 ml) followed by addition of 28% sodium methoxide/methanol (0.5 ml), and the mixture was refluxed for 3 hours. To this reaction mixture was added a large quantity of water and the resulting crystals were rinsed with water and dried under reduced pressure to provide 20 mg (yield 39%) of the title compound. 1H-NMR (CD3OD) δ: 3.73(3H,s), 3.97(3H,s), 5.70(2H,s), 7.41(2H,d,J=8.4Hz), 7.51(2H,d,J=8.8Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 8.36(1H,s).