Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=2)O1>>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Reactant: CC1(C)OB(c2ccc(NC(N)=O)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(N)=O)cc2)nc2c1CN(CC1CC1)C2

Procedure:
Method as described for example 47 using intermediate 8 and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. Purified by prep. LCMS (high pH) and (low pH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=1.[CH:31](=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH2:18][CH3:31])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)ccc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC=O
Product: CCN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](C(=O)NC)C(C)(C)C)C1

Procedure:
Compound 65 was prepared according to the procedure described for the synthesis of compound 64 by replacing formaldehyde with acetaldehyde. LCMS (+ESI) m/z=434.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:13])=[CH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:23](=[O:25])[CH3:24])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: Nc1ccc2ccc(C(F)(F)F)cc2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-trifluoromethyl-2-aminonaphthalene (550 mg, 2.60 mmol) and triethylamine (1.09 mL, 7.81 mmol) in dichloromethane (10 mL) at room temperature is added acetyl chloride (0.222 mL, 3.13 mmol) dropwise. After stirring at room temperature for 1.5 hours, the mixture is partitioned between dichloromethane and water. The organic layer is washed with 0.1 M citric acid solution, brine, dried (MgSO4) and concentrated by rotary evaporator to give 7-trifluoromethyl-2-acetamidonaphthalene as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]([OH:22])=O)[C:14]=3[CH:23]=2)=[CH:6][CH:5]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:26]1([C:20](=[O:22])[CH2:19][O:18][C:15]2[C:14]3[CH:23]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:24])=[CH:9][CH:8]=4)[CH:11]=[CH:12][C:13]=3[O:17][N:16]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetic acid (50 mg, 0.142 mmol) was dissolved in 3 mL DMF. Pyrrolidine (30 mg, 0.425 mmol) was added followed by addition of HATU (81 mg, 0.212 mmol). The mixture was stirred at ambient temperature overnight, then diluted with 60 mL ethyl acetate, washed with water and brine, and evaporated. The product was purified on 12 g silica gel with 0-100% ethyl acetate in hexane followed by recrystallization from acetonitrile/water to give the title compound (30 mg, 0.073 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[NH3:12]>O>[F:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH2:12])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: N
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Solvent: O
Product: Nc1cc(F)cc2cc[nH]c12
Temperature: 155 °C

Procedure:
A mixture of 7-bromo-5-fluoro-indole (1 g), Cu (0.31 g), CuBr (0.64 g) and NH3 (30 ml of a 33% aqueous solution) was heated in an autoclave for 1.5 h at 155° C. The mixture was diluted with water and extracted with EtOAc. The organic phase was dried and the solvent removed to give 5-fluoro-7-amino-indole as an oil which was used without further purification. UPLC/MS found for C8H7FN2 as (M+H)+ 151.0.
Reaction SMILES: CN([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])C.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[O:17]=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]
Reactant: CN(C)CC1CCCCC1=O
Reactant: O=C1CCCC1
Product: O=C1CCCCC1CC1CCCC1=O
Yield: 80 %

Procedure:
2-(oxo-cyclopentyl)methyl cyclohexanone is prepared from 2-(dimethylaminomethyl)-cyclohexanone and cyclopentanone according to the method described in Ann.Chim., 1963, 53 (6), 819 and is isolated as a colourless oil in 80% yield b.p. 92°/0.05 mm. 5,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline is prepared from 2-(2-oxocyclopentyl)methylcyclohexanone according to the method described in Ann.Chim., 1963, 53, (6), 819 and is isolated in 65% yield as a colourless oil b.p. 80°/0.05 mm. The hydrochloride is prepared for characterisation by treating an ethereal solution of the base with ethereal HCl and is isolated as the hemihydrate as colourless needles from ethanol-ether m.p. 104° C (Found: C, 65.7; H, 7.8; N, 6.6. C12H16N.HCl.1/2H2O requires: C, 65.8; H, 7.8; N, 64%. 5,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta[b]-quinoline is converted to methyl 5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline-5-carboxylate following the method described in Example 19 and this is converted to 5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]-quinoline-5-carboxamide following the method described in Example 22. The amide is converted to the title compound, following the procedure of Example 23, and is recrystallised from isopropanol, dissolved in ether and treated with an excess of ethereal HCl. The resultant solid is recrystallised from ethanol-ether to give the hydrochloride of the title compound as the monohydrate m.p. 118° C. (Found: C, 54.6; H, 6.3; N, 10.0. C13H16N2S.HCl H2O requires: C, 54.4; H, 6.6; N, 9.8%)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](I)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:30]2[CH:31]=[CH:32][O:28][CH:29]=2)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C)nc1I
Reactant: OB(O)c1ccoc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C)nc1-c1ccoc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation V, and 3-furanboronic acid, the desired product is obtained in the form of a white solid (yield=42%).
Reaction SMILES: F[C:2](S(OC)(=O)=O)(F)F.[OH:10][CH:11]([CH2:18][C:19]([O:21]CC)=O)[CH2:12][C:13](OCC)=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.Cl>C(Cl)Cl.C1COCC1>[CH3:2][O:10][CH:11]([CH2:18][CH2:19][OH:21])[CH2:12][CH2:13][OH:14]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CC(O)CC(=O)OCC
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(CCO)CCO
Temperature: -5 °C
Reaction time: 16 h

Procedure:
25 ml of methyl trifluoromethylsulfonate are added to a solution of 30 g of diethyl 3-hydroxyglutarate and 33 ml of 2,6-di-tert-butylpyridine in 500 ml of DCM and the mixture is refluxed for 5 hours. After cooling, 500 ml of a 0.5N solution of HCl are added, the organic phase is decanted and dried over magnesium sulfate and the solvent is evaporated off under vacuum. The solid obtained is taken up with 200 ml of anhydrous THF, the mixture is filtered and the filtrate is then cooled to -5° C. 160 ml of a 1M solution of lithium aluminum hydride in THF are then added slowly and the mixture is stirred for 16 hours, the temperature being allowed to rise to RT. The reaction mixture is cooled to 0° C. and 5.5 ml of water, 18 ml of a 15% solution of NaOH and 5.5 ml of water are added successively. The mineral salts are filtered off and the filtrate is evaporated under vacuum to give the expected product after distillation under reduced pressure. B.p.=104° C. under 1.5 Pa.
Reaction SMILES: Cl.C([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])(C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([CH3:31])[C:21]=1[CH3:32].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([NH:9][C@@H:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]([OH:6])=[O:17])(=[O:28])=[O:29])=[C:22]([CH3:31])[C:21]=1[CH3:32]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 0.5 g of L-phenylalanine t-butyl ester hydrochloride in 4 mL of N,N-dimethylformamide were added 0.67 g of 4-methoxy-2,3,6-trimethylphenylsulfonylchloride and 0.96 mL of N,N-diisopropylethylamine. After stirring for 2 hours at room temperature the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in 16 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. After stirring for 2 h at room temperature the reaction mixture was concentrated. Dichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture was basic), the aqueous layer separated and washed with dichloromethane. The aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropanoic acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.97 and 1.99 (3H, 2× s), 2.12 and 2.17 (3H, 2× s), 2.45-3.54 (8H, m), 2.49 (3H, s), 3.81 and 3.85 (3H, 2× s), 3.82-3.92 (1H, m), 5.13-5.28 (1H, m), 6.61 (1H, s), 6.84-7.07 (5H, m), 7.17-7.21 (1H, m), 7.50-7.56 (1H, m), 7.65-7.69 (1H, m), 7.76-7.82 (1H, m), 8.30-8.35 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][CH:7]=1
Reactant: Fc1cc(-c2cncc(NCC3CCOCC3)n2)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (375 mg, 1.162 mmol), DMSO (3.5 ml) and trans-4-aminocyclohexanol (1204 mg, 10.46 mmol) was stirred at 100° C. for 18 hours and the progress was followed by LCMS. The reaction mixture was let cool, added 300 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (3×), water (2×), saturated salt solution (1×), dried with sodium sulfate, filtered and concentrated to crude solid. The crude material was purified by silica gel chromatography using 40 g column, eluting slowly from (80% ethyl acetate 20% heptane with 2% MeOH) to 100% ethyl acetate with 2% MeOH. The desired fractions are concentrated to a constant mass, lyapholized from 1:1 ACN/water (does not fully dissolve), re-lyophilized from 80 ml of (60/40) ACN/water solution with sonicating to dissolve solid, giving 270 mg of title compound as free base. LCMS (m/z): 418.3 (MH+), retention time=0.52 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.19-1.55 (m, 6H) 1.71 (d, J=12.89 Hz, 2H) 1.85-2.15 (m, 5H) 3.28-3.32 (dMeOH, 2H App.) 3.40 (td, J=11.72, 1.76 Hz, 2H) 3.50-3.73 (m, 2H) 3.94 (dd, J=11.28, 3.08 Hz, 2H) 6.66 (s, 1H) 7.86 (s, 2H) 7.99 (s, 1H)
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:30][C:31]([CH2:33][Cl:34])=[O:32])C=CC=CC=1>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:30][C:31]([CH2:33][Cl:34])=[O:32])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: O=C(CCl)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)CCl)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 6.6 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 150 ml of benzene is treated at room temperature with 9 g of triphenylchloroacetonylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (7:3). There is obtained methylene-(2S,5R)-6-(3-chloroacetonylidene)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as an orange oil [Rf: 0.4; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm); 1.21 (9H); 1.51 (3H); 1.57 (3H); 4.25 (2H); 4.65 (1H); 5.9 (m, 2H); 6.1 (1H); 6.93 (1H)].
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[Cu]I>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CN2CCC1CC2
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 110 °C
Reaction time: 40 h

Procedure:
Under N2, the mixture of 3-hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol), 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), CuI (Strem Chemicals, 0.38 g, 2 mmol) and 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol) in toluene (anhydrous, Aldrich, 50 mL) was stirred at 110° C. for 40 h. After the reaction went to completion, the reaction mixture was diluted with chloroform (100 mL) and washed with water (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (300 MHz, CD3OD) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCl/NH3) m/z 330 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([NH:48][CH:49]2[CH2:51][CH2:50]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([N:48]([C:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:10])[CH:49]2[CH2:50][CH2:51]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1cnc(Cl)nc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-chloropyrimidine-5-carboxylic acid (2.00 g), ethyldiisopropylamine (6.39 mL), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (4.21 g) in tetrahydrofuran (15 mL) is stirred for 45 min at room temperature prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.94 g). The resulting mixture is stirred at room temperature for 1 h. The solvent is evaporated in vacuo and the residue purified by HPLC(H2O/MeOH/TFA). LC (method 3): tR=1.89 min; Mass spectrum (ESI+): m/z=381/383 (Cl) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH:25]1([C:23]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)=[N:15]3)=[C:20]([CH3:21])[N:22]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)C3CCCCC3)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(C4CCCCC4)n3n2)cc(OC)c1OC
Yield: 25.9 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[3,4,5-tris(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclohexane-carboxamide (Intermediate 68) (140 mg, 0.34 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.25 mL, 2.68 mmol), to afford 7-cyclohexyl-5-methyl-N-[3,4,5-tris(methyloxy)phenyl]-imidazo[5,1-f][1,2,4]triazin-2-amine (35 mg) as a yellow solid. MS m/z 398 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]([OH:34])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([OH:34])([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:25][CH2:24]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCC(O)(CC)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Product: CCC(O)(CC)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 3-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)pentan-3-ol were reacted to give 316. LCMS m/z: 533.3 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:53]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[O:21])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)O)cs2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)N3CCCCCC3)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
3-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.075 g, 0.24 mmol) was dissolved in DMF (2 mL). Triethylamine (0.72 mmol), HATU (0.26 mmol) and homopiperidine (0.26 mmol) were added and the reaction stirred at room temperature overnight. The reaction mixture was purified directly by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.066 g). LCMS m/z 393.26 [M+H]+ RT=4.05 min (Analytical Method 4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=3)[CH:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2ccn(-c3ccc(SC)cc3)c2c1
Yield: 47 %

Procedure:
In the same manner as in Reference Example 89 and using 1-bromo-4-(methylthio)benzene instead of methyl 2-chloroisonicotinate and methyl 1H-indole-6-carboxylate instead of 2-aminopyridine, the title compound (yield 47%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][C:16]1([CH3:30])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][C:19](=[O:28])[CH2:18][C:17]1=[O:29].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([CH:18]1[C:17](=[O:29])[C:16]([CH3:30])([CH3:15])[CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][C:19]1=[O:28])=[O:5]
Reactant: CC1(C)C(=O)CC(=O)CC1c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2Cl)C(=O)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
2-Chloro-4-(methylsulfonyl)benzoyl chloride (2.3 g, 9 mmol) and 4,4-dimethyl-5-phenyl-1,3-cyclohexanedione (2.0 g, 9 mmol) were dissolved in 50 ml of acetonitrile. Triethylamine (1.8 g, 18 mmol) was added dropwise and the resulting solution was stirred at room temperature for 1 hour. Acetone cyanohydrin (0.17 g, 2 mmol) and triethylamine (1.8 g, 18 mmol) were added and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was concentrated under vacuum and the residue dissolved in 100 ml of methylene chloride. The methylene chloride solution was washed with 2N hydrochloric acid, 10% cupric acetate, water, 5% potassium carbonate, 2N hydrochloric acid, and water. The methylene chloride solution was dried over anhydrous magnesium sulate and concentrated under vacuum, yielding 1.2 g of the desired product as a viscous oil. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.