Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:43][C:31]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH2:30][CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)CC(C)(CCCCBr)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC(C)(CCCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
0.2 g (0.574 mmol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-yl-amide, 0.15 g (0.5 mmol) of methyl 6-bromo-2-methyl-2-phenyl-hexanecarboxylate and 0.083 g (0.6 mmol) of potassium carbonate are dissolved in 10 ml of acetonitrile. The mixture is stirred for 8 hours at 60° C. and for 14 hours at ambient temperature. Then the reaction mixture is poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off in the rotary evaporator. After column chromatography on silica gel (eluant: dichloromethane/methanol=20:1) a highly viscous oil remains.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(Br)c(F)c1[N+](=O)[O-]
Product: COc1ccc(Br)c(Oc2ccccc2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 1, Step 1, using 1-bromo-2-fluoro-4-methoxy-3-nitrobenzene and phenol as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)n2cc(F)c(N)nc2=O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To commercially available 4-amino-5-fluoro-pyrimidin-2-ol (1.0 grams (g), 7.75 millimoles (mmol)) in acetonitrile (CH3CN; 50 milliliters (mL)) was added bis-N, O-trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated at 70° C. for 1 hour (h), resulting in a clear solution. After cooling to room temperature, 4-methoxybenzene-1-sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (EtOAc) and brine. The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield the product as a pale yellow solid (1.48 g, 64%): mp 182-185° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (br s, 1H), 8.11 (d, J=5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.02-6.96 (m, 2H), 5.77 (br s, 1H), 3.88 (s, 3H); ESIMS m/z 300 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:55]([Si:59]([CH3:70])([CH3:69])[O:60][C:61]1[CH:62]=[C:63]([CH:66]=[CH:67][CH:68]=1)[CH2:64][NH2:65])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:65][CH2:64][C:63]2[CH:66]=[CH:67][CH:68]=[C:61]([O:60][Si:59]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:69])[CH3:70])[CH:62]=2)=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
To a solution of 3-Chloro-thiophene-2,5-dicarboxylic acid 2-methyl ester (500 mg, 2.27 mmol) in anhydrous DMF (10 mL) was added triethylamine (1.0 mL, 6.81 mmol), HBTU (1.03 g, 2.72 mmol), HOBT (370 mg, 2.72 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (650 mg, 2.72 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-30% EtOAc in hexane to afford the desired product (0.26 g, 26% yield).
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH:16]([N-]C(C)C)([CH3:18])[CH3:17].[Li+].C(Br)C=C.Cl>O1CCCC1>[OH:1][C:2]1[CH:11]([CH2:18][CH:16]=[CH2:17])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1=C(O)CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1Cc2ccccc2C(C(=O)OC)=C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a stirred solution of 3,4-dihydro-2-hydroxynaphthalene carboxylic acid, methyl ester (36.2 g, 177 mmol) in dry tetrahydrofuran (440 ml) at -30° C. under argon was added dropwise lithium diisopropylamide (195 ml, 2M solution, 390 mmol). Allyl bromide (24.3 ml, 284 mmol) was then added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h, then treated with hydrochloric acid (5M) to pH2-3. The resulting mixture was extracted with ethyl acetate (2×1000 ml) and the combined extracts were washed with brine (1000 ml), dried (Na2SO4) and evaporated in vacuo to give the title compound as a brown oil (46.1 g).
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1=[O:20])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[C:5]1=[O:20]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CN1CCCCCC(N=[N+]=[N-])C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCCCC(N)C1=O

Procedure:
Dissolve 9.5 g. 3-azido-1-t-butoxycarbonylmethylperhydroazocin-2-one in 85 ml. ethanol. Hydrogenate at 40 psi hydrogen pressure at room temperature using 1.0 g. 10% palladium on charcoal as catalyst. Filter the reaction and concentrate the filtrate to obtain 3-amino-1-t-butoxycarbonylmethylperhydroazocin-2-one.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][NH:6][CH3:7].[C:8]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([N+:21]([O-:23])=[O:22])([CH2:14]3)[CH2:12]1)[CH2:18]2)(O)=[O:9]>CN(C=O)C>[CH3:5][N:6]([CH3:7])[C:8]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([N+:21]([O-:23])=[O:22])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9]
Reactant: CNC
Reactant: O=C(O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CN(C)C(=O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-nitroadamantane obtained by the method of Example 43 was dissolved in 10 ml of DMF. To the mixture, 15 mmole of acetyl chloride was added dropwise over 30 minutes. The mixture was heated to begin to reflux around the conclusion of the addition. After refluxing for 2 hours, the mixture was cooled,and 25 mmole of dimethylamine was added dropwise over 30 minutes while retaining the temperature of the mixture at 10° C. or less followed by stirring for more 2 hours. As a result, the conversion of 1-carboxy-3-nitroadamantane was 99%, and 1-(N,N-dimethylcarbamoyl)-3-nitroadamantane (yield 95%) was formed.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1Cl>>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1
Reactant: CNC(=O)Nc1cc(CN)ccn1
Reactant: COC(=O)c1cccnc1Cl
Product: CNC(=O)Nc1cc(CNc2ncccc2C(=O)OC)ccn1
Temperature: 120 °C
Yield: 62.8 %

Procedure:
A mixture of 1-(4-aminomethyl-pyridin-2-yl)-3-methyl-urea (3.8 g, 21.1 mmol) and 2-chloro-nicotinic acid methyl ester [Mann et al. J. Chem. Soc.; 1952; 2057, 2060] (1.78 g, 10.4 mmol) was heated for 1 hour at 120° C. The crude product was purified by chromatography on silica gel (Gradient elution: 100% CH2Cl2 to 93% CH2Cl2/7% MeOH) to give 2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinic acid methyl ester (2.06 g); Mp. 145-146° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([O:32]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42]>>[CH2:41]([N:43]([CH2:44][CH3:45])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([OH:32])=[CH:16][CH:17]=3)[O:12]2)=[CH:9][CH:10]=1)[CH3:42]
Reactant: COc1ncc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)c(OC)n1
Reactant: CCNCC
Product: CCN(CC)CCOc1ccc(C2Oc3cc(O)ccc3C(C)=C2c2cnc(OC)nc2OC)cc1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and diethyl amine as the starting material.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]>O.C(O)C>[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A solution of sodium hydroxide (2.23 g, 55.9 mmol) in water (100 mL) was added to a solution of ethyl 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate (14.6 g, 43.0 mmol) in ethanol (100 mL). The reaction mixture was stirred at room temperature overnight, then the ethanol was removed under reduced pressure. The remaining aqueous solution was washed with dichloromethane and adjusted to pH 5 with 10% aqueous hydrochloric acid. The aqueous layer was extracted with dichloromethane (2×). The later organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to yield 11.5 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoic acid as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:25]([CH2:24][CH2:23][Cl:22])(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 5-(tert-butoxycarbonylamino)pentylamine (1.00 g, 4.94 mmol) and triethylamine (689 pt g, 4.94 mmol) in dichloromethane (22 mL) at 0° C. was added 2-chloro-1-ethanesulfonyl chloride (470 μL, 4.50 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give the title compound (100% yield), which was used in the next step without further purification.
Reaction SMILES: [O-]Cl=O.[Na+].[OH2:5].[CH2:6]([C:13]1([CH2:19][CH:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O.CCOCC>[CH2:6]([C:13]1([CH2:19][C:20]([OH:5])=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O
Reactant: O=CCC1(Cc2ccccc2)C=CCCC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C(O)CC1(Cc2ccccc2)C=CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of NaH2PO4 (55.3 g), NaClO2 (36.3 g), DMSO (200 mL) and water (375 mL) was added a solution of 3-benzyl-3-formylmethylcyclohexene (57 g) in DMSO (150 mL) during a 3 hour period. After addition, the mixture was stirred overnight and diluted with ether (200 mL). This was extracted with saturated NaHCO3 (3×100 mL). The combined aqueous layer was cooled to 0° C. and acidified to PH=1 with conc. HCl. This was extracted with CH2Cl2 (3×300 mL). The combined organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as thick oil (50 g). MS (MH+=231).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[NH:14][N:13]=[C:12]([C:15](O)=[O:16])[C:11]=1[N+:18]([O-:20])=[O:19])([CH3:9])[CH3:8].C[N:22](C)C=O>ClCCl>[CH:7]([C:10]1[NH:14][N:13]=[C:12]([C:15]([NH2:22])=[O:16])[C:11]=1[N+:18]([O-:20])=[O:19])([CH3:9])[CH3:8]
Reactant: CC(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (6.8 ml, 77.6 mmol) was added dropwise to a suspension of 5-isopropyl-4-nitro-1H-pyrazol-3-carboxylic acid (5.15 g, 25.9 mmol) in dichloromethane (80 ml) containing dimethylformamide (0.1 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 1 hours, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in toluene (100 ml) and ammonia gas was bubbled into the solution for 2 hours. The reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was dissolved in hot methanol (300 ml). The resultant precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was azeotroped with water (300 ml), concentrated to approximately 80 ml under reduced pressure and the precipitate was isolated by filtration. This was washed with water and dried under to give 5-isopropyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (3.1 g) as an orange solid. 1H NMR (400 MHz, DMSO-D6): δ=7.94-7.99 (1H, brs), 7.68-7.72 (1H, brs), 3.45-3.55 (1H, m), 1.24-1.30 (6H, d) ppm. LRMS (electrospray): m/z [M+Na]+ 221, [M−H]+ 197.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Product: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Temperature: 120 °C

Procedure:
Piperazine (23.69 g, 8 mol. equiv.) was melted and 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see International Patent Application Publication no. WO93/19059) (8.64 g, 34.4 mmol) added. The mixture was heated at 120° C. for 15 hours under nitrogen. The reaction was cooled to room temperature and the excess piperazine removed under reduced pressure. The residue was then chromatographed on silica gel using gradient elution (methanol:dichloromethane 1:19 changing to 1:4, by volume) to give the title compound (6.32 g). LRMS m/z=242 (m+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([N:28]([CH2:38][CH3:39])[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1)[CH3:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:38][CH3:39])[CH2:26][CH3:27])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)CCCC1CCCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCC1CCCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2-(3-diethylaminopropyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.09 minutes; C29H37Cl2N5O2 (558.55); mass spectrum: (M−H)−=558/560 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[I:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH:15]=[C:14]([I:13])[CH:18]=[N:17]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2cc(I)cn2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, 4-iodopyrazole and cesium carbonate in NMP. EI-MS m/e (%): 359 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[Cl:1][C:2]1[N:7]=[C:6]([O:22][CH2:21][CH2:20][O:19][CH3:18])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: COCCO
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Agent: [Na]
Product: COCCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred solution of 44.6 g (0.176 mol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine from Example 1 in 300 ml of 2-methoxyethanol at 0°-5° was added dropwise over 2 hours a solution of 4.25 g (0.177 g-atom) of sodium metal in 250 ml of 2-methoxyethanol. The solution was stirred for 30 minutes at 5°, concentrated and the resulting oil dissolved in 500 ml of ethyl acetate. The solution was washed with water, dried over sodium sulfate, filtered and concentrated to give 40.4 g (0.137 mol, 78%) of 2-chloro4-(2-methoxyethoxy)-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine: m.p. 50°-52°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1.[CH2:16]1[C:19]2([CH2:22][CH2:21][CH2:20]2)[CH2:18][C:17]1=[CH:23][C:24]#[N:25].C1CCN2C(=NCCC2)CC1>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([C:17]3([CH2:23][C:24]#[N:25])[CH2:18][C:19]4([CH2:22][CH2:21][CH2:20]4)[CH2:16]3)[CH:9]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1
Reactant: Clc1cc2nccn2c(-c2cn[nH]c2)n1
Reactant: N#CC=C1CC2(CCC2)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
7-Chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation M, Step A; 0.380 g, 1.73 mmol), 2-(spiro[3.3]heptan-2-ylidene)acetonitrile (Example 160, Steps A-C, 0.461 g, 3.46 mmol) and DBU (0.130 mL, 0.865 mmol) were suspended in MeCN (10 mL) and stirred at ambient temperature overnight. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2-3% (9:1 MeOH:NH4OH)/DCM to provide 2-(2-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.493 g, 1.40 mmol, 81% yield). MS (apci) m/z=353.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[F:31])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][C:12]1[N:13]=[C:14]([O:16][CH3:17])[N:15]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:39](=[O:41])[CH3:40])[CH:9]=[CH:8][CH:7]=2)[CH:11]=1
Reactant: CC(=O)Cl
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCN)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCNC(C)=O)c2)n1
Reaction time: 0.17 h

Procedure:
A solution of {6-[3-(2-amino-ethyl)-phenyl]-2-methoxy-pyrimidin-4-yl}-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [150 mg, 0.35 mmol, see Example 64, step 2] and triethylamine (0.24 mL, 1.73 mmol) in DCM (5 mL) is treated with acetyl chloride (54 mg, 0.69 mmol) at 10° C. After 10 min at 10° C., the mixture is quenched with aqueous NaHCO3 solution (8 mL), and filtered through Chem-Elut with CH2Cl2 washing (10 mL). The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 80% EtOAc in Heptane to 5% MeOH in CH2Cl2 to give N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-acetamide hydrochloride [70 mg, Example 65]. LCMS: RT=2.2 minutes, MS: 477 (M+H); 1H NMR (300 MHz, CDCl3) □9.1 (1H, s), 7.95 (1H, brs), 7.7-7.4 (7H, m), 6.65 (1H, s), 4 (3H, s), 3.8-3.75 (2H, m), 3.3 (2H, q, J=6.9 Hz), 3.04 (2H, t, J=6.6 Hz), 2.78 (2H, t, J=7.5 Hz), 2.49 (3H, s). IC50=37 nM
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.Cl[CH2:9][CH2:10][NH2:11]>>[CH3:1][C:2]1[N:3]([CH2:9][CH2:10][NH2:11])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: NCCCl
Agent: Cl
Product: Cc1nccn1CCN
Yield: 47 %

Procedure:
2-(2-Methylimidazol-1-yl)ethylamine was prepared from 2-methylimidazole and 2-chloroethylamine hydrochloride using the method described in Step B of Example 1. This material was obtained as a light yellow oil in 47% yield. 1H NMR (300 MHz, CD3OD) δ 6.95 (br s, 1H), 6.82 (br s, 1H), 4.90 (bs, 2H), 3.90 (t, J=6.9 Hz, 2H), 2.93 (t, J=6.9 Hz, 2H), 2.35 (s, 3H); MS (APCI) m/z 126 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[CH:18][C:17]([CH:20](Br)[CH3:21])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[N:5]1)([CH3:3])[CH3:2].[C:24]([O-:27])(=[O:26])[CH3:25].[K+]>C(O)(=O)C>[C:24]([O:27][CH:20]([C:17]1[CH:18]=[N:19][C:10]([C:6]2[NH:7][C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:23])[N:5]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:21])(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc(C(C)Br)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(C)OC(C)=O)cnc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A mixture of 12 g of methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(1-bromoethyl)nicotinate, 3.1 g potassium acetate and 30 mL acetic acid is stirred under nitrogen and heated at reflux for 8 hours. The reaction mixture is filtered, and the filtrate is concentrated in vacuo. The residue is triturated with ether, filtered, and concentrated in vacuo to give the desired product as an amber glass.