Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:13])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:16]1=[O:27].CCN(C(C)C)C(C)C.Cl[C:38]1[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=1>CN(C=O)C>[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:13])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:22][CH2:23][N:24]([C:38]3[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=3)[CH2:25][CH2:26]2)[C:16]1=[O:27]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 50.8 %

Procedure:
(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (2.6 g, 6.1 mmol) was dissolved in DMF (30 mL) and DIEA (3.2 mL, 18 mmol) and 2-chloro-5-ethylpyrimidine (1.1 g, 8.0 mmol) were added and heated at 100° C. overnight. The reaction was concentrated and purified over silica gel (25-100% EtOAc in hexanes) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (1.5 g, 3.1 mmol, 51% yield) as a white solid. Mass spectrum (apci) m/z=494.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:23](=[O:24])[CH:22]([Br:21])[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: CC(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: To 2.7 g of indoline-2-carboxylic acid ethyl ester and 3.4 g of powdered potassium carbonate in 30 ml of methylene chloride, 2.42 g of 2-bromopropanoyl chloride in 10 ml of methylene chloride are added during 2 minutes. The mixture is stirred at room temperature for 2 hours and then partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed twice with 30 ml of 1N hydrochloric acid and 25 ml of saturated aqueous sodium chloride, dried and evaporated, to yield the 1-(2-bromopropanoyl)-indoline-2-carboxylic acid ethyl ester melting at 101°-103°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=2[CH3:35])=[O:28])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)#[N:2].[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:13])=[CH:10][CH:9]=1)[CH:17]1[CH2:18][CH2:19][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:34]([CH3:35])=[N:33][CH:32]=[N:31][C:30]=2[CH3:36])=[O:28])[CH2:21][CH2:22]1)#[N:2]
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: C1CNCCN1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Yield: 31.2 %

Procedure:
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 133) (54 mg, 0.10 mmol) and piperazine (26 mg, 0.30 mmol) afforded COMPOUND 135 as a white solid (19 mg, 31%). 1H NMR (CDCl3) δ 0.83-1.13 (m, 2H), 1.03 (d, 3H, J=6.3 Hz), 1.49-1.79 (m, 5H), 2.20 (t, 1H, J=11.7 Hz), 2.51 (s, 6H), 2.60 (t, 1H, J=10.8 Hz), 2.76-2.86 (m, 7H), 3.29-3.37 (m, 1H), 3.58-3.72 (m, 4H), 3.82-3.88 (m, 1H), 3.96 (s, 2H), 6.52 (d, 2H, J=8.7 Hz), 7.25-7.26 (m, 2H), 7.44-7.56 (m, 4H), 8.54 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.46, 21.97, 29.16, 30.38, 30.82, 39.97, 41.22, 42.71, 43.57, 46.25, 48.11, 51.94, 55.66, 60.20, 112.14, 112.70, 118.91, 124.15, 129.38, 129.45, 129.70, 130.77, 130.90, 141.23, 149.34, 157.56, 163.12, 166.27, 170.60. ES-MS m/z 609 (M+H). Anal. Calcd. for C35H44N8O2.0.5CH2Cl2.0.1H2O: C, 65.29; H, 6.98; N, 17.16. Found. C, 65.22; H, 7.12; N, 16.78.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=2[CH2:9][O:8]1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:16][C:15]2[C:10]3[CH2:9][O:8][CH2:7][C:11]=3[CH:12]=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cccc2c1COC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3c2COC3)cc1
Temperature: 100 °C

Procedure:
A suspension of potassium carbonate (670 mg, 4.85 mmol), 1,3-dihydro-2-benzofuran-4-ol (Intermediate 2, 110 mg) and 1-fluoro-4-nitrobenzene (114 mg, 0.808 mmol) in N,N-dimethylformamide (DMF) (5 ml) was heated under microwave irradiation at 100° C. for 3×30 minutes. The mixture was concentrated. 2 ml of water were added and then dichloromethane. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The organic phase was dried over sodium sulphate and concentrated under vacuum to afford the title compound, which was directly used in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.CC1(C)[O:37][C@H:36]([CH2:38][N:39]2[C:43]([CH3:44])=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=[N:40]2)[CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].O.[ClH:62].CCOCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:21])[F:22])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:42]3[CH:41]=[N:40][N:39]([CH2:38][C@@H:36]([OH:37])[CH2:35][OH:34])[C:43]=3[CH3:44])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12].[ClH:62]
Reactant: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@@H]1COC(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C[C@@H](O)CO
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50.0 mg, 0.0962 mmol), 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (46.50 mg, 0.1443 mmol), Pd(PPh3)4 (5.558 mg, 0.004810 mmol), K2CO3 (39.89 mg, 0.2886 mmol) and 4:1 dioxane:H2O (2 mL, 20 mmol) was heated to 95° C. for 2 h. The solution was cooled to rt, and 12 M of HCl in H2O (0.08017 mL, 0.9620 mmol) was added. The material was concentrated in vacuo, and extracted with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel and purified via column chromatography, eluting with 3-6% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in MeOH, and 2.0 M of HCl in Et2O (0.4810 mL, 0.9620 mmol) was added at rt. The solution was concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.85 (d, J=7.1 Hz, 3H), 2.27 (s, 3H), 3.52-3.63 (m, 2H), 4.00-4.08 (m, 1H), 4.11-4.19 (m, 1H), 4.26 (dd, J=14.1, 4.3 Hz, 1H), 5.12 (q, J=7.2 Hz, 1H), 6.44 (br. s., 1H), 7.14 (dd, J=8.8, 4.5 Hz, 1H), 7.20 (t, J=8.7 Hz, 1H), 7.37-7.43 (m, 2H), 7.52 (s, 1H), 8.16 (d, J=2.0 Hz, 1H). MS (ES+): m/z=495.11/497.11 (100/50) [MH+]. HPLC: tR=1.29 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1F
Solvent: C1CCOC1
Product: OCc1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of 3-bromo-2-fluorobenzoic acid (Fluorochem; 500 mg; 2.28 mmol) in anhydrous THF (4 mL) was slowly treated with borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) and the resulting solution was stirred at RT for 2 days. Borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) was added and the reaction mixture was stirred at RT for a further 3 hours. The reaction was carefully quenched with water and the mixture was concentrated. The residue was dissolved in Et2O, and the aqueous phase was saturated with K2CO3. The organic layer was separated and the aqueous phase was extracted with Et2O. The combined organic phases were washed with water and brine, dried over MgSO4 and concentrated to dryness affording the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15].C([N-]C(C)C)(C)C.[Li+]>>[CH3:16][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([CH:5]1[CH2:4][CH:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:2]([CH3:1])[C:6]1=[O:7])=[O:28])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN1C(=O)CC[C@H]1c1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CC(c2cccnc2)N(C)C1=O

Procedure:
The title compound was prepared from (-)-cotinine (5.0 g, 0.028 mol), 2,6-diisopropylphenyl isocyanate (5.69 g, 0.028 mol) and lithium diisopropylamide (0.028 mol) using the procedure described in Example 1.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([F:16])[F:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12]Br)[CH:6]=2.C[N+]1([O-])CC[O:29]CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:14]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([F:16])[F:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]=[O:29])[CH:6]=2
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2cc(CBr)ccc2cc1Br
Reactant: C[N+]1([O-])CCOCC1
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)C(F)(F)c1cc2cc(C=O)ccc2cc1Br
Yield: 86.6 %

Procedure:
To a solution of diethyl [3-bromo-7-(bromomethyl)-2-naphthyl](difluoro)methylphosphonate (0.2 g from step 5, example 2) in 5 mL, of dioxane was added N-methylmorpholine N-oxide (0.17 g). The reaction mixture was refluxed for 1 h. The mixture was quenched with a saturated solution of NH4Cl and the mixture was extracted with EtOAc and the extract dried over Na2SO4 and evaporated. The residue was purified by flash chromatography eluting with 10-20% EtOAc/hexanes to afford diethyl (3-bromo-7-formyl-2-naphthyl)(difluoro)methylphosphonate (0.15 grams) which was hydrolyzed with TMSBr (2 mL) in CH2Cl2 (1 mL) at rt. overnight. The mixture was evaporated to dryness and the residue was dissolved in ethanol. It was evaporated to dryness again and the process was repeated 3 times. The reaction residue was dissolved in water and treated with NaOH 1N to afford the titled product as a sodium salt.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[I:13](O)(=O)=O.II.[S].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[I:13][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=1
Reactant: Cc1ccn(-c2cccnc2)n1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(-c2cccnc2)cc1I
Temperature: 70 °C
Yield: 212 %

Procedure:
To a mixture of 3-(3-methyl-1H-pyrazol-1-yl)pyridine (6.7 g, 42.1 mmol), iodic acid (2.96 g, 16.84 mmol), and diiodine (8.55 g, 33.7 mmol) in acetic acid (60.1 ml) was added concentrated sulfur acid (3.74 ml, 21.04 mmol). The reaction mixture heated to 70° C. for 30 minutes. The reaction mixture was poured onto ice with sodium thiosulfate and was extracted with diethyl ether. The combined organic phases were washed with saturated aqueous sodium bicarbonate. The organic phases were then dried with magnesium sulfate, filtered and concentrated in vacuo. The solid residue was dissolved in dichloromethane, applied to a 80 g silica gel column, and eluted with 0-80% acetone in hexanes to afford 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)pyridine (11.3 g, 35.7 mmol, 85%) as a white solid: mp 131° C.; 1H NMR (400 MHz, CDCl3) δ 8.95-8.85 (m, 1H), 8.52 (dd, J=4.8, 1.4 Hz, 1H), 8.00-7.94 (m, 1H), 7.91 (s, 1H), 7.38 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 2.34 (s, 3H); EIMS m/z 285.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:14](O)[CH2:15][OH:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([C:10]1([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[O:16][CH2:15][CH2:14][O:13]1)[CH3:12]
Reactant: CCC(=O)c1ccc2occc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1(c2ccc3occc3c2)OCCO1
Yield: 87.2 %

Procedure:
A solution of 1-(benzofuran-5-yl)propan-1-one (650 mg, 1.0 eq), ethane-1,2-diol (3.5 g, 15.0 eq) and 4-methylbenzenesulfonic acid (65 mg, 0.1 eq) in 20 mL toluene was refluxed for 72 h, cooled, quenched with sat. NaHCO3 (aq) and extracted with EtOAc. The extract was washed with brine, dried, concentrated, and purified by column chromatography to give the desired product (710 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.0 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.4 Hz, 1.6 Hz, 1H), 6.76 (dd, J=2.4 Hz, 0.4 Hz, 1H), 4.02-4.05 (m, 2H), 3.78-3.81 (m, 2H), 1.96 (q, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[C:24]#[CH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:25][C:24]#[CH:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
A mixture of 2.0 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoro methyl-6(1H)-pyrimidinone, 1.06 g of propargyl bromide and 1.64 g of potassium carbonate in 5.0 ml of anhydrous acetone is heated at boiling point for 2.5 hours while stirring. The insoluble constituents are subsequently filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of ethyl acetate and the solution is extracted three times with 50 ml of water each time. The organic phase is then dried over anhydrous sodium sulphate and evaporated to dryness. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 108°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH:12]([NH:16][C:17]([O:19][CH3:20])=[O:18])[CH:13](C)C)[CH:7]([C:22]2[NH:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[NH:42][C:43]([CH:46]6[CH2:50][CH2:49][CH2:48][N:47]6[C:51](=[O:61])[CH:52]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]([CH3:55])[CH3:54])=[N:44][CH:45]=5)=[CH:37][CH:36]=4)=[CH:29][CH:28]=3)[N:26]=2)[CH2:6]1)=[O:4].N[C@H](C(O)=O)C(C)C.C(=O)([O-])N.N[C@H](C(O)=O)C>>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH:12]([NH:16][C:17]([O:19][CH3:20])=[O:18])[CH3:13])[CH:7]([C:22]2[NH:23][CH:24]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[NH:42][C:43]([CH:46]6[CH2:50][CH2:49][CH2:48][N:47]6[C:51](=[O:61])[CH:52]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]([CH3:55])[CH3:54])=[N:44][CH:45]=5)=[CH:37][CH:36]=4)=[CH:31][CH:32]=3)[N:26]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Agent: CC(C)[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NC(=O)[O-]
Product: COC(=O)NC(C)C(=O)N1CCN(C(=O)OC)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1

Procedure:
(example DS) was prepared in a similar fashion to 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-piperazine-1-carboxylic acid methyl ester (example DP), replacing the valine derived carbamate with the corresponding alanine derived carbamate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:4][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[F:31][C:32]1[CH:66]=[CH:65][C:35]([C:36](/[N:38]=[C:39]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:37])=[CH:34][CH:33]=1.FC1C=CC(C(N=C=S)=O)=CC=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:36](/[N:38]=[C:39]2/[N:18]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([C:25](=[O:26])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[C:3]3[CH:4]=[C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:37])=[CH:65][CH:66]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCCN3CCOCC3)ncc2N)CC1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Agent: O=C(N=C=S)c1ccc(F)cc1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OCCCN4CCOCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(5-amino-2-(3-morpholinopropoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide with 1.3 equivalents of 4-fluorobenzoyl isothiocyanate. Isolated as an off-white solid (98 mg, 104% yield). M/Z calc'd for C30H39FN6O4: 566.67. found 567 [M+H].
Reaction SMILES: C(OC(=O)C)(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:16][C:17](=[O:19])[O:23][C:21](=[O:22])[CH2:20]2)=[CH:13][CH:14]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccc(F)cc2)CC(=O)O1
Yield: 76.1 %

Procedure:
To acetic anhydride (5 ml) was added 3-(4-fluorophenyl)glutaric acid (2.00 g, 8.84 mmol) and the mixture was refluxed for 3 hours. The resulting mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-hexane to obtain 1.4 g (yield 76%) of the title compound. mp. 99–104° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])[CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1cncc(Br)c1
Product: Clc1ccccc1-c1cncc(Br)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 2-chlorophenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:30])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C)nc1-c1ccc(Cl)cc1Cl
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-ethyl-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.76–0.82, 1.02–1.34, 1.56–1.58, 2.24, 2.62, 3.38–3.55, 3.90–3.95, 5.22, 5.50–5.54, 6.14–6.16, 6.70–6.72, 7.04–7.62; MS (ESI+) for C24H25Cl2N3O m/z 443 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)(=[O:4])=[O:3]
Reactant: OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methanesulphonyl chloride (2.4 ml) was added dropwise to an ice-cooled solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butan-1-ol (8.13 g) (see Preparation 28) and triethylamine (5.32 ml) in dichloromethane (100 ml) under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. and then 90 minutes at room temperature before being washed twice with water. The organic phase was separated, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give the crude product. This was chromatographed on silica gel eluting with 95:5, by volume, dichloromethane:diethyl ether to give 1-methanesulphonyloxy-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (8.85 g) as a yellow oil and as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[CH:21][C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]1[CH2:35][CH2:34][N:33]2C(=NC[CH2:31][CH2:32]2)CC1>N1CCCCC1>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[CH:21][C:22]([N:33]3[CH2:32][CH2:31][CH2:25][CH2:35][CH2:34]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: C1CCNCC1
Product: O=C1c2cccc3c(N4CCCCC4)ccc(c23)C(=O)N1OCc1ccccc1

Procedure:
2-Benzyloxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.8 g, 2.1 mmol, from Example M) was reacted in piperidine (3.0 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.8 g of 2-benzyloxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.0 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) afforded 0.28 g of the title compound, mp 222-224° C.;