Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([CH2:11]Cl)=[CH:6][N:5]=1>CC(C)=O>[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([CH2:11][I:1])=[CH:6][N:5]=1
Reactant: ClCc1cnc(Cl)nc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ncc(CI)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 500-mL, round-bottom flask equipped with a magnetic stirrer, condenser, and nitrogen-inlet bubbler was charged with sodium iodide (38.5 g, 256.9 mmol) (Aldrich) and acetone (300 mL). After a clear solution was obtained, 2,4-dichloro-5-(chloromethyl)pyrimidine (50.0 g, 253.2 mmol) (from Example 1b supra) was added in one portion. After stirring at room temperature for 20 minutes, the mixture was heated to reflux for 15 minutes. NMR analysis indicated 98% conversion. After cooling to room temperature, the resulting precipitate (sodium chloride) was removed by filtration through a medium-sintered glass funnel and washed with acetone. The combined filtrate and washes were concentrated to a weight of ca. 75 g. The resulting concentrated solution of 2,4-dichloro-5-(iodomethyl)pyrimidine in acetone was diluted with toluene (20 mL). After concentration to a weight of ca.85 g in order to remove the residual acetone, this concentrated solution of 2,4-dichloro-5-(iodomethyl)pyrimidine in toluene was used directly in the next step.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[N:28]3[C:23]([CH:24]=[CH:25][CH:26]=[C:27]3[CH3:29])=[C:22]([C:30]#[N:31])[CH:21]=2)[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[C:30]([C:22]1[CH:21]=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:11]2=[O:32])[N:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[CH3:29])#[N:31]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C#N)c3cccc(C)n23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C#N)c3cccc(C)n23)c2ccccc21
Reaction time: 12 h

Procedure:
To a solution of 3-[3-(1-Cyano-5-methyl-indolizin-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (30 mg, 0.067 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (3.2 mg, 0.14 mmol) at room temperature. The solution was stirred at the same temperature for 12 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that precipitate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product 1 (19 mg, 67%). LCMS (ESMS): m/z 417.28 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C@H:40]1[CH2:39][CH2:38][C@H:37]([NH:36][C:33]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]=2[CH3:32])=[O:34])[CH2:42][CH2:41]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23](Cl)[N:22]=1.C1(C)C=CC=CC=1>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([F:29])([F:30])[F:28])=[C:21]([Cl:20])[N:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a suspension of tert-butyl-1-piperazine carboxylate (27.0 g, 145 mmol) and K2CO3 (40.0 g, 290 mmol) in DMSO (200 mL) were 2,6-dichloro-3-trifluoromethylpyridine (29.1 g, 135 mmol) and toluene (50 mL) added. The thick slurry was stirred at 80° C. for two hours, followed by addition of toluene (0.5 L) and water (1 L). The phases were separated and the organic phase was washed twice with water. The solvent from the dried (MgSO4) organic phase was evaporated at reduced pressure. The solid residue was recrystallized from EtOAc/heptane to give white crystals (37 g). The filtrate from the recrystallization was concentrated and the residue chromatographed on a column of silica with hexane/EtOAc (90:10) to give further 6.0 g of product (total yield 85%). Purity 99% (HPLC); mp 125° C. Anal. (C15H19ClF3N3O2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([O:23]CC)=[O:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([OH:23])=[O:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2)sc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2)sc2c1CCCC2
Temperature: 120 °C
Yield: 21.6 %

Procedure:
A solution of ethyl 2-(4-fluorobenzenesulphonylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylate (Intermediate 2, 0.12 g) and lithium hydroxide monohydrate (0.036 g) in a mixture of dioxane and water (2:1, 6 ml) was divided between two 2-5 ml microwave vials and the contents of each vial were stirred and heated in the microwave at 120° C. for 30 minutes. The two batches were combined, diluted with water and extracted with ethyl acetate. The aqueous phase was acidified to pH1 by addition of hydrochloric acid (1M) and the resultant suspension was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and DCM (2.5%) to give a solid which was triturated with DCM. The resultant solid was collected by filtration to give 2-(4-fluorobenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.024 g) as a light orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:14]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:57])([F:56])[F:55])[CH:48]=2)[N:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:26][CH2:27]5)=[CH:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:55])([F:56])[F:57])[CH:48]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(OC(F)(F)F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(Cc2cccc(OC(F)(F)F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 80 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(3,5-dimethyl-1-(3-(trifluoromethoxy)benzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (140 mg, 0.174 mmol) was hydrolyzed by lithium hydroxide (36.7 mg, 0.27 mmol), THF/Methanol/water (2/3/1 ml) to afford 90 mg (80.3% yield) of the titled compound. LCMS: m/z=647.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([CH3:10])[N:3]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:13])=[O:8])[N:4]([CH3:10])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(Cl)cc1C(=O)O
Solvent: c1ccccc1
Product: Cn1nc(Cl)cc1C(=O)Cl

Procedure:
100 g of 3-chloro-1-methyl-5-pyrazole-carboxylic acid (the Compound No. 4.1 (a) of the present invention) were suspended in 200 ml of benzene, and 150 ml of thionyl chloride were added thereto dropwise. Then, the mixture was heat-refluxed for 4 hours. The reaction mixture was allowed to cool, and the solvent was then distilled off under reduced pressure. The resulting residue was distilled under reduced pressure to obtain 103 g of the intended 3-chloro-1-methyl-5-pyrazolecarbonyl chloride.
Reaction SMILES: NC1C=C(C(C2C=C3C(C(C=CC4C=CC=CC=4)=NN3COCC[Si](C)(C)C)=CC=2)=C)C=CC=1.[C:35]([NH:38][C:39]1[CH:40]=[C:41]([C:45]([C:47]2[CH:55]=[C:54]3[C:50]([C:51]([CH:64]=[CH:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[N:52][N:53]3COCC[Si](C)(C)C)=[CH:49][CH:48]=2)=[CH2:46])[CH:42]=[CH:43][CH:44]=1)(=[O:37])[CH3:36]>C(OCC)(=O)C.CCCCCC>[C:35]([NH:38][C:39]1[CH:40]=[C:41]([C:45]([C:47]2[CH:55]=[C:54]3[C:50]([C:51]([CH:64]=[CH:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)=[N:52][NH:53]3)=[CH:49][CH:48]=2)=[CH2:46])[CH:42]=[CH:43][CH:44]=1)(=[O:37])[CH3:36]
Reactant: C=C(c1cccc(NC(C)=O)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: C=C(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C(c1cccc(NC(C)=O)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
6-(1-(3-Aminophenyl)-vinyl)-3-styryl 1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazole was converted to 6-(1-(3-acetamido-phenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazole as described for Example 12(a): Rf sm 0.42, p 0.26 (ethyl acetate-hexane 4:6); FTIR (thin film) 3305, 3059, 2952, 1667, 1608, 1585, 1555, 1486, 1448, 1433, 1369, 1306, 1249, 1076, 912, 859, 836, 748, 693 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H, J=8.5 Hz), 7.7-7.4 (m, 9H), 7.35 (m, 2H), 7.26 (dd, 1H, J=1.3, 8.4 Hz), 7.16 (bd, 1H, J=7.8 Hz), 5.75 (s, 2H), 5.62 (s, 1H), 5.61 (s, 1H), 3.66 (t, 2H, J=8.2 Hz), 2.16 (s, 3H), 0.98 (t, 2H, J=8.2 Hz), −0.02 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 169.8, 150.9, 144.6, 143.5, 142.8, 142.0, 139.4, 138.6, 132.9, 130.3, 129.3, 127.9, 125.6, 124.2, 123.7, 122.0, 121.3, 121.0, 117.1, 110.8, 68.0, 25.8, 19.1, 0.0; HRMS (FAB) [M+Na]/z Calc'd 532.2396, found 532.2410.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[I-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30]>C(O)C.CC(C)=O>[N:7]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:21](=[O:30])[C:22]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]3[C:24]2=[O:25])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCCCN1CCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
Potassium carbonate (13.57 g, 98.20 mmol), pyrrolidine (4.47 ml, 54.01 mmol) and sodium iodide (7.359 g, 49.098 mmol) were added to ethanol/acetone (1:1) at room temperature and stirred for 1 hour. To the reaction mixture was slowly added N-(5-bromopentyl)phthalimide (2) (10.60 g, 49.10 mmol), and the resulting reaction mixture was refluxed at 50° C. for 24 hours. After the reaction was completed, the resulting white solid was filtered and the solvent was evaporated under reduced pressure. Afterwards, the obtained residue was extracted with a saturated 1N NaOH aqueous solution and dichloromethane three times. Then, the organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: dichloromethane:methnol:ammonia water=100:9:1) to give the target compound (3.27 g, 45%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:4]([CH3:15])[CH:3]=1.S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]2[S:9][CH2:10][CH2:11][C:12](=[O:14])[C:6]=2[C:7]=1[CH3:8]
Reactant: Cc1cc(SCCC(=O)O)c(C)cc1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1SCCC2=O
Temperature: 5 °C
Yield: 87.8 %

Procedure:
19.50 g (67.4 mmol) of the title compound of Step A was dissolved in 156 mL of dichloromethan and cooled to 5° C. 78 mL of concentrated sulfuric acid was added dropwise over 45 minutes with vigorous stirring and the reaction was then allowed to stir at 5° C. for 1.5 hours. The reaction was poured into 500 mL of ice water, the layers were separated and the aqueous phase extracted twice with 300 mL of dichloromethane. The combined organic layers were washed twice with 1.0 N NaOH, once with water. dried over magnesium sulfate and concentrated under reduced pressure to yield 16.04 g of the title compound of Step B as a yellow solid melting at 86-87° C. 1H NMR (CDCl3): δ2.26 (s, 3H), 2.59 (s, 3H), 3.00 (t, 2H), 3.19 (t, 2H), 7.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.C(=O)=O.[NH3:18]>C1COCC1>[Cl:1][C:2]1[C:11]([NH2:18])=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2
Reactant: N
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cc1C
Agent: O=C=O
Solvent: C1CCOC1
Product: Cc1cc2nc(N)c(Cl)nc2cc1C
Temperature: 100 °C

Procedure:
A mixture of 2,3-dichloro-6,7-dimethyl-quinoxaline (30 g) in 300 mL of THF was cooled with dry-ice in a sealed vessel. Ammonia gas was added for 10 min, then the mixture was heated to 100° C. for 20 h. After removal of the solvent in vaccuo the residue was purified by flash chromatography to yield 14 g of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ=7.43 (1H, s), 7.37 (1H, s), 7.00 (2H, s), 2.28 (6H, s) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:2]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH2:60])[C:55]([CH3:61])=[CH:54]2>CN(C=O)C.O.CCOC(C)=O>[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH:60][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:8][CH:9]=1)=[O:15])[C:55]([CH3:61])=[CH:54]2
Reactant: Cc1cc2cc(F)ccc2n1N
Reactant: O=C(O)c1cnc(-c2cccnc2)nc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cc(F)ccc2n1NC(=O)c1cnc(-c2cccnc2)nc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (506 mg, 2.13 mmol), HCTU (970 mg, 2.34 mmol), and DIPEA (1 mL, 5.72 mmol) in DMF (10 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-2-methyl-indol-1-ylamine (311 mg, 1.89 mmol) is added. The resulting mixture is stirred at 75° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 45% EtOAc in heptane to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)-amide (300 mg, 46%) as a solid. MS: 348 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 9.60 (d, 1H), 9.49 (s, 2H), 8.82-8.76 (m, 2H), 7.64 (dd, 1H), 7.39 (dd, 1H), 7.29 (dd, 1H), 6.94 (dt, 1H), 6.35 (s, 1H), 2.33 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][OH:14].Cl.C([O-])(O)=O.[Na+].CO>O>[OH:14][NH:13][C:11](=[NH:12])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(Cc1ccc([N+](=O)[O-])cc1)NO
Temperature: 25 °C

Procedure:
A 250-mL round bottomed flask was charged with 2-(4-nitrophenyl)acetonitrile (2.5 g, 15.4 mmol, 1 eq.), NH2OH/HCl (2.12 g, 31 mmol, 2 eq), NaHCO3 (2.82 g, 2.3 mol, 7 eq.), MeOH (100 ml) and water (16 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure. The residue was treated with water (100 ml). Solid was collected by filtration and washed with water (3×20 ml) followed by dichloromethane (3×10 ml). After drying, the title compound was obtained as yellowish solid (2.46 g, 84% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2Cl)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=1.C(=O)(O)[O-].[Na+].CC(O)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2[NH:31][CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([O:23][CH3:22])[CH:29]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2Cl)cc1
Reactant: COc1cc(CN)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(CNc2nnc(Cl)cc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide (162 mg, 0.5 mmol), C-(2-Methoxy-pyridin-4-yl)-methylamine (211 mg, 1 mmol), and sodium bicarbonate (840 mg, 20 mmol) were added to IPA (2.5 mL). The reaction was ran in microwave (150° C., 15 min). Water (5 mL) was added to the reaction and the mixture was extracted with DCM (2×5 mL). The organic layer was dried over sodium sulfate and reduced. The crude was subjected to Flash chromatography (2% MeOH/DCM) for further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:13])[C:8]=1[Si:9]([CH3:12])([CH3:11])[CH3:10])[NH2:5].[CH2:14]([N:17]([CH2:31][CH:32]=[CH2:33])[CH:18]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1)[C:19](O)=[O:20])[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH2:31]([N:17]([CH2:14][CH:15]=[CH2:16])[CH:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=1)[C:19]([NH:5][C:4]1[CH:6]=[C:7]([F:13])[C:8]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[C:2]([F:1])[CH:3]=1)=[O:20])[CH:32]=[CH2:33]
Reactant: C[Si](C)(C)c1c(F)cc(N)cc1F
Reactant: C=CCN(CC=C)C(C(=O)O)c1ccc(COC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCN(CC=C)C(C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1)c1ccc(COC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (5 g, 24.84 mmol), 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (8.21 g, 29.81 mmol), DMAP (3.34 g, 27.32 mmol) and DIEA (21.69 mL, 124.20 mmol) in ethyl acetate (150 mL) was added T3P (29.2 mL, 49.68 mmol), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give 2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide (6.79 g, 14.81 mmol, 59.6%) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].C1COCC1.[CH3:38][NH2:39]>C(Cl)Cl.CN(C=O)C.O>[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:39][CH3:38])=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Yield: 32 %

Procedure:
Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringe wise to 4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoic acid (150 mg, 0.40 mmol, prepared in example 4) in CH2Cl2 (10 mL) while stirring under nitrogen at room temperature. Immediately, 1 drop of DMF was added by pipette initiating a foaming of the mixture. The reaction was stirred one hour at this temperature and then concentrated under reduced vacuum to yield a white semi-solid. This material was placed into THF (10 mL) and added dropwise to a stirring solution of 40% methylamine in water (5 mL) at room temperature and the mixture was stirred overnight. In the morning, the solution was concentrated under reduced vacuum and the resulting oil was taken into CH2Cl2 and the organic layer was washed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 159 mg as a semi-solid. This material was purified via silica gel chromatography employing the Chromatotron and using a 2000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 1:1 to yield the title compound (51 mg, 32%) as a white solid. Ion spray M.S. 393.1 (M*+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15]Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].[Na]>CO.O>[CH2:1]([O:8][C:9]1[C:10]([CH2:15][O:18][CH3:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ncccc1OCc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COCc1ncccc1OCc1ccccc1
Yield: 97 %

Procedure:
The solution of 41 g (0.18 mol) of 3-(benzyloxy)-2-(chloromethyl)pyridine in 100 ml of methanol is added to the solution of sodium methoxide, prepared by adding 5.2 g (0.23 mol) of sodium to 150 ml of methanol. After refluxing for 3 hours under nitrogen, the solution is concentrated to dryness. The oil obtained is taken up in water and extracted with ethyl acetate. The organic solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate, and then concentrated to dryness. 39 g (97%) of a brown oil are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: OB(O)c1cccc(F)c1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4cccc(F)c4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (250 mg, 0.62 mmol) and 3-fluorobenzene-boronic acid (173 mg, 1.24 mmol) were reacted as described in Example 61. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 gave 3-[2-(3-fluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 464 (M+H+).