Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H]>C(O)C.Cl.[Pt]=O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: COCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COCCC1CCNCC1

Procedure:
4-(2-Methoxyethyl)pyridine (9.6 g), in a mixture of ethanol (100 ml) and 2 N hydrochloric acid (30 ml) was hydrogenated over platinum oxide at 50°/50 p.s.i. until uptake of hydrogen ceased. The catalyst was removed by filtration and the solution evaporated in vacuo. The residue was then dissolved in water (50 ml), basified to pH 8 with dilute sodium hydroxide, and extracted with chloroform. The aqueous phase was evaporated in vacuo to give an oil which solidified on cooling. The solid was triturated with ether (60 ml), collected by filtration and dissolved in the minimum quantity of boiling ethyl acetate. The hot solution was filtered and on cooling deposited hygroscopic crystals of 4-(2-methoxyethyl)piperidine (9.9 g), m.p. 108°-110°. The structure was verified by i.r. and n.m.r. spectroscopy.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9]12([C:19](Cl)=[O:20])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.C(OCC)C>C(N(CC)CC)C>[C:9]12([C:19]([C:5]3[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=3)=[O:20])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)c1n[nH]c(C(=O)C23CC4CC(CC(C4)C2)C3)n1

Procedure:
To a cooled, stirred mixture of 2 g. of 1,2,4-triazole-3-carboxamide and 5.4 g. of adamantylcarbonyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23.5 hours. The mixture is filtered and the solid is washed successively with diethyl ether, cold water, diethyl ether and dried in vacuo for 3 hours yielding 4.5 g. of colorless solid. This solid is extracted with hot dry acetonitrile, cooled and washed with acetonitrile yielding 0.4 g. of colorless crystals. The remaining 3.5 g. of acetonitrile insoluble solid is further extracted with acetonitrile, yielding an additional 0.6 g. of product, m.p. 213°-216° C. (dec.).
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1N.[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13].[OH-].[Na+]>O>[ClH:1].[ClH:1].[NH:14]([C:12]1[N:4]([CH3:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:13]=1)[C:15]([NH2:17])=[NH:16]
Reactant: N#CNC(=N)N
Reactant: CNc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(NC(=N)N)nc2ccccc21
Yield: 42 %

Procedure:
A mixture of N-methyl-o-phenylenediamine dihydrochloride (10.80g. 0.005 mol) and cyanoguanidine (9.30g, 0.11 mol) was heated under reflux in water (80 ml) for 21/2 hours. The reaction mixture was cooled, basified with excess 40% sodium hydroxide, and the resulting precipitate filtered, washed with water and dried in vacuo. (7.19g; m.p. 142°-146°C). This was dissolved in excess dilute hydrochloric acid and evaporated in vacuo. The crude hydrochloride was recrystallised from ethanol/ether to yield 2-guanidino-1-methylbenzimidazole dihydrochloride (600g; 42%) as off-white micro-crystals m.p. 228°-238°C.
Reaction SMILES: [OH:1]O.[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:29])[CH2:7]1)[CH:4]=[CH2:5].[OH-].[Na+].Cl>C(O)C>[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]([NH2:25])=[O:1])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:29])[CH2:7]1)[CH:4]=[CH2:5]
Reactant: OO
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C#N)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(N)=O)c2)C[C@H]1C
Temperature: 60 °C
Yield: 79 %

Procedure:
Hydrogen peroxide (0.5 mL of a 30% by weight solution) was added to a mixture of the benzonitrile (0.50 g, 1.4 mmol), 0.7 mL of 10N aqueous sodium hydroxide and 3 mL of ethanol. The reaction was exothermic with gas evolution and formation of a white precipitate. After a few minutes, the mixture was carefully heated under a reflux condenser in an oil bath at 60° C. for three hours. After cooling to room temperature, 6N aqueous hydrochloric acid was added to adjust the pH to 8. The mixture was evaporated to dryness under vacuum, and the residue was extracted between ethyl acetate and pH 8 buffer solution. The organic layer was washed with pH 8 buffer and brine, dried over sodium sulfate, and the solvent was evaporated to give 0.42 g (79%) of (±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide as a bright yellow solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O1CCOCC1.O>[CH3:32][C@H:30]1[O:29][C@H:28]([CH3:33])[CH2:27][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:31]1
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H](C)O1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (109.5 mg, 0.225 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (148 mg, 0.450 mmol) and sodium bicarbonate (56.7 mg, 0.675 mmol) in 1,4-Dioxane (5 mL) and Water (1.5 mL) stirred in air at room temp was added solid Solvias Catalyst (12.60 mg, 0.022 mmol). The reaction mixture was stirred at 120° C. for 2 hr. After this time, sodium hydroxide solution (2N, 0.5 mL) was added and the reaction mixture left to stir at room temperature for two hours. On cooling, the reaction mixture was passed through a celite cartridge (10 g) and washed with ethyl acetate. The resulting solution was evaporated and the crude residue purified by MDAP (Method C). Appropriate fractions were combined and concentrated in vacuo to afford the title compound (43 mg).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C(OCC)(=O)C>[Cl:1][C:2]([C:3]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=[CH:17][CH:18]=[CH:19]1)=[O:4])([Cl:7])[Cl:6]
Reactant: Clc1ccc(-c2ccc[nH]2)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(C(Cl)(Cl)Cl)C1(c2ccc(Cl)cc2)C=CC=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A solution of trichloroacetyl chloride (11.26 g, 0.0619 mol) in ether is treated with a solution of 2-(p-chlorophenyl)pyrrole (10.0 g, 0.0503 mol) in ether, stirred for four hours at room temperature, treated with saturated potassium carbonate solution and diluted with ethyl acetate. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow solid. The solid is recrystallized from 2-propanol to give the title product as a yellow solid (12.63 g, mp 166°-168° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:38]2[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Product: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (60 mg, 0.11 mmol) as described in Reference Example 17 and 4-trifluoromethylbenzeneboronic acid (Lancaster, 24 mg, 0.13 mmol HPLC Rt=4.76 min. 1H-NMR 500 MHz (CDCl3): 4.13 (s, 3H), 6.55 (m, 1H), 6.68 (m, 1H), 7.07 (q, J=10 Hz, 1H), 7.28 (m, 3H), (7.50 m, 3H), 7.61 (d, J=10 Hz, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C=O.[C:24]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH3:24])[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
309 mg (1.07 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) was added dropwise in a 100 ml recovery flask, and dissolved in 9.2 ml of anhydrous methanol. 0.134 ml of a formaldehyde aqueous solution (35%) was then added to the solution. 201.7 mg of sodium cyanoborohydride was then added to the mixture. After the addition of acetic acid to adjust the mixture to pH 5.0, the mixture was stirred at room temperature for 24 hours. 1 mol/l sodium hydroxide aqueous solution was then added to the mixture, followed by extraction with chloroform. The extract was dried over magnesium sulfate and concentrated, thereby obtaining 296.2 mg of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b) was obtained as a colorless oily substance (yield: 92%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][OH:8])[N:6]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][O:8][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1sc(N)nc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N)nc1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 2.0 g (9.8 mmol) of ethyl 2-amino-4-(hydroxymethyl) -1,3-thiazole-5-carboxylate (Intermediate 209) and 1.3 g (19.4 mmol) of imidazole in 20 ml DMF was added 1.6 g (10.6 mmol) of t-butyldimethylsilyl chloride. After stirring for 2 h, solvent was removed and the residue was taken up in water. Insoluble solids were collected, ground up, washed with water and dried in vacuo to afford 2.95 g of product. MS (ES) (MH+): 317 for C13H24N2O3SSi; NMR (d6-DMSO): 0.03 (s, 6H), 0.86 (s, 9H), 1.2 (t, 3H), 4.1 (q, 2H), 4.8 (s, 2H), 7.8 (s, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(F)c(F)c1
Reaction time: 3 h
Yield: 54 %

Procedure:
14.4 g of sodium hydride as a 60% dispersion in oil are suspended in 250 ml of THF and cooled in a water bath. A solution of 50 g of 3,4-difluorophenylacetonitrile in 50 ml of THF is added dropwise, the mixture is then left to stand for 3 hours at RT and a solution of 68.16 g of 2-(2-bromoethoxy)tetrahydropyran in 100 ml of THF is added dropwise. After one night at RT, the mixture is acidified with a buffer of pH 2, the THF is evaporated off and the residue is taken up with water and extracted with ether. The extract is washed twice with a buffer solution of pH 4 and then with water and with saturated sodium chloride solution. It is decanted and the organic phase is dried over MgSO4 and concentrated under vacuum. The residue is chromatographed on silica using pure toluene and then toluene containing up to 3% of AcOEt as the eluent to give 49.5 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:43])(=[O:42])[CH3:41]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:43])(=[O:42])[CH3:41]
Reactant: CC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: CC(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of acetic acid (0.034 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 4 h and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then a sample (1 mL) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give Nilotinib acetate form I.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=[CH:17][CH:16]=2.S(Cl)([Cl:29])=O>O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([Cl:29])=[O:26])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.1 g (0.0147 mole) of 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionic acid and 7.0 g (0.059 mole) of thionyl chloride in 200 ml tetrahydrofuran is stirred for 18 hours at room temperature. The solvent is then removed in vacuo to give 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:22][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Nc3ccccc3)c2nc1OC
Reaction time: 40 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and aniline 80 μL (0.84 mmol). Reaction was continued for 40 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 180 mg (62%), mp 238-240° C.; 1H NMR (CDCl3): δ 8.34 (s, 1H), 7.81 (d, 2H, J=8.8 Hz), 7.69 (s, 1H), 7.35 (t, 2H, J=7.6, 8.5 Hz), 7.11 (t, 1H, J=6.3, J=7.3 Hz), 4.17 (s, 3H), 4.02 (s, 3H), 2.58 (s, 3H); (APCI): m/z 369 (M+H). Anal. Calcd. for C18H16N4O5: C, 58.69; H, 4.38; N, 15.21. Found: C, 58.62; H, 4.52; N, 15.06.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][C:12]1([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.BrC1C(NCCNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1(CN)CCCC1
Agent: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)NC1(CNc2nc(Cl)ncc2Br)CCCC1

Procedure:
tert-butyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamate was synthesized by treating 5-bromo-2,4-dichloropyrimidine with tert-butyl N-[1-(aminomethyl)cyclopentyl]carbamate using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI) 405 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[N:19]([C:22]1[N:27]=[C:26]([C:28](OC)=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=1)[CH2:20][CH3:21].[OH-].[Na+]>C1COCC1.CCOCC>[Br:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:13]=[CH:12][C:11]=1[N:19]([CH2:20][CH3:21])[C:22]1[N:23]=[C:24]([CH3:32])[CH:25]=[C:26]([C:28]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:29])[N:27]=1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(=O)N2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 26 h
Yield: 39.4 %

Procedure:
To sodium hydride (60% in oil, 0.24 g, 6.0 mmol) suspended in anhydrous THF (10 mL) was added morpholine (0.52 g, 6.0 mmol) with stirring; the reaction mixture was warmed to reflux temperature and stirred for 1 hour. The reaction mixture was then cooled to ambient temperature and 2-(N-(2-bromo-4-(2-propyl)-phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-pyrimidine (2.0 g, 5.1 mmol) was added. Stirring was continued for 26 hours. The reaction mixture was then poured onto a 1 N NaOH solution, stirred and extracted three time with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (Et2O) afforded the title compound as a solid (900 mg, 39% yield): mp 145° C.; NMR (CDCl3, 300 MHz): d 7.5 (d, 1H, J=1), 7.2 (dd, 1H, J=7.1), 7.1 (d, 1H, J=7), 6.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.3 (m, 11H), 3.1-3.0 (m, 1H), 2.9 (septet, 1H, J=7), 1.3 (d, 6H, J=7), 1.15 (t, 3H, J=7); Anal. (C21H27BrN4O2) Calcd: C, 56.38, H, 6.08, N, 12.52, Br, 17.86; Found: C, 56.07, H, 6.05, N, 12.29, Br, 18.08.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccnc(C#C[Si](C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 2-chloro-4-methoxypyrimidine (2.60 g, 17.99 mmol), ethynyltrimethylsilane (3.05 mL, 21.58 mmol), tetrahydrofuran (24 mL) and triethylamine (12.53 mL, 89.90 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then copper(I) iodide (0.14 g, 0.72 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.51 g, 0.72 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath at 90° C. After 16 hours, the mixture was filtered and the solvent was removed under reduced pressure. The residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated, washed with 4% aqueous sodium hydrogencarbonate solution, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (9:1 hexane/ethyl acetate) gave the title compound (2.85 g, 77%) as an oil.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N+:13]1[CH:14]([C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:16][C:17]=1OCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:32][N+:33]([O-:35])=[O:34]>C(Cl)Cl>[CH3:24][O:23][C:21]([CH:14]1[CH2:15][CH2:16][C:17](=[CH:32][N+:33]([O-:35])=[O:34])[N:13]1[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:22]
Reactant: CCOC1=[N+](Cc2ccccc2)C(C(=O)OC)CC1
Reactant: C[N+](=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To the mixture obtained in Example 1C (0.2 mol) in 130 mL CH2Cl2 at ambient temperature was added Et3N (33.5 mL, 0.24 mol) followed by CH3NO2 (13 mL, 0.24 mol). The mixture stirred at ambient temperature for 8 h then was diluted with CH2Cl2, the layers were separated and the organic layer was washed with 20 mL 5% H2SO4 and 20 mL brine. The organic layer was dried over anhydrous Na2SO4, concentrated and purified via column chromatography (SiO2, 50% hexanes-EtOAc) to give 10.2 g of the title compound (36.9 mmol). MS (DCl/NH3) m/z 277 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([OH:17])=[C:12]([F:18])[CH:11]=2)=[O:9])[CH:7]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([F:18])[C:13]([O:17][CH3:22])=[C:14]([F:16])[CH:15]=2)=[O:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cc(F)c(O)c(F)c1)c1cc(Br)ccc1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)cc(C(=O)c2cc(Br)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
To a solution of (5-bromo-2-chlorophenyl)(3,5-difluoro-4-hydroxyphenyl)methanone (600 mg, 1.7 mmol) in acetone (5 mL) was added iodomethane (50 μL, 2.6 mmol) and potassium carbonate (470 mg, 3.4 mmol), and the mixture was stirred overnight at 25° C. After the volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (30 mL), washed with brine, and concentrated to give 629 mg of crude product, which was used in the next step without further purification.