Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22]>C(OCC)(=O)C>[OH:22][CH2:21][CH2:23][NH:24][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:3]=1
Reactant: NCCO
Reactant: CCn1cnc2c(Nc3cccc(F)c3)nc(Cl)nc21
Solvent: CCOC(C)=O
Product: CCn1cnc2c(Nc3cccc(F)c3)nc(NCCO)nc21

Procedure:
0.2 g (0.62 mmol) of 2-chloro-9-ethyl-6-(3-fluoro-phenyl-amino)-9H-purine (prepared according to Stage 90.2) is stirred in 1 ml of ethanolamine at 150° C. for 3 h, and the mixture is allowed to cool and is diluted with ethyl acetate. The organic phase is washed with water, separated off and dried over sodium sulfate. On concentration, 2-(2-hydroxy-ethyl-amino)-6-(3-fluoro-phenyl-amino)-9-ethyl-9H-purine is obtained as a crystalline precipitate. This precipitate is filtered off and dried; m.p. 184° C.; FAB-MS: (M+H)+=317; Rf=0.5 (CH2Cl2:methanol=9:1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.[NH2:25][C@@H:26]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH:40]1([CH2:39][C@H:26]([NH:25][C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:10]3[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=3)[CH:4]=2)=[O:9])[CH2:27][N:28]2[C:29](=[O:38])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]2=[O:37])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (138 mg, 0.62 mmol), N,N-diisopropylethylamine (0.541 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (285 mg, 0.581 mmol, 94% yield) as a white foam: LCMS (ES) m/e 491, 493 (M, M+2)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5](=[O:17])[NH:4][C:3]=1[C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C.[CH:40]1([N:45]=[C:46]=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH:40]1([NH:45][C:46]([N:4]2[C:3]([C:18]3[N:19]([C:23]4[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=4)[CH:20]=[CH:21][N:22]=3)=[C:2]([CH3:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[C:5]2=[O:17])=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: Cc1c(-c2nccn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C=NC1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2nccn2-c2ccc(C#N)cc2)n(C(=O)NC2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
4-[5′-Methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-2′,3′-dihydro-1′H-[2,4′]biimidazolyl-1-yl]-benzonitrile (Example 59, 108 mg, 0.26 mmol) was suspended in dry DCM (5 ml) and DIPEA (130 μl, 3 eq.) was added followed by cyclopentyl isocyanate (90 μl, 88 mg, 0.79 mmol). The mixture was heated and stirred at 45° C. for 24 h. The solvent was removed in vacuo and the residue purified by chromatography eluting with EtOAc, thereby yielding the title compound (100 mg, 73%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[C:9]([F:15])[CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][C:9]=1[F:15]
Reactant: NCc1ccc(Br)cc1F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl chloroformate (85.0 μL, 1.1 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol) and triethylamine (148.1 μL, 1.1 mmol) in methylene chloride (5 mL) at 0° C. After 10 min, the ice-water bath was removed. The mixture was stirred at RT for 1 h, washed with water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (220 mg, 83.9%) was directly used in next step without further purification. LCMS: (M+H)=263.9/261.8.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([F:15])=[C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][NH2:26]>O1CCOCC1>[F:8][C:7]1[C:2]([NH:25][NH2:26])=[N:3][C:4]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:5]([F:15])[C:6]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: NN
Reactant: Fc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Solvent: C1COCCO1
Product: NNc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Temperature: 100 °C

Procedure:
4-[2,3,5-Trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine (1.2 g; 3.5 mmol) and hydrazine (2 g) were added to dioxane (10 mL) and heated to 100° C. for six hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (20 mL) and washed with a 10% sodium carbonate solution (2 mL). It was dried over magnesium sulfate, and evaporated, to give crude [3,5-Difluoro-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine. The crude product was then dissolved in ethanol. To the solution was added one drop of acetic acid, and m-tolylaldehyde (600 mL; 5 mmol) and it was heated at 60° C. overnight. The solvent was then evaporated, and the residue was purified by column chromatography to give Compound 12 (850 mg). Theoretical Mass Ion: 461.1; observed MH+peak: 462.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COCCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield an off-white solid (44%). LCMS: m/z=525.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J=5.8 Hz), 7.63 (m, 2H), 7.45 (d, 1H, J=4.3 Hz), 7.27 (m, 1H), 7.03 (m, 1H), 6.03 (m, 2H), 5.97 (m, 2H), 4.36 (m, 1H), 3.74 (m, 4H), 3.38 (d, 3H, J=5.6 Hz), 3.06 (bs, 1H), 2.89 (bs, 1H), 2.51 (m, 1H), 2.30 (m, 3H), 2.03 (m, 2H), 1.62 (m, 1H), 1.33 (bs, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[NH:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Product: CN(C)CCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(2-Dimethylamino-ethylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared from 1-t-butoxycarbonyl-iso-nipecotic acid (5 g), iso-butylchloroformate (2.83 mL) and N,N-dimethyl-1,2-ethylenediamine (2.63 mL). Exact mass calculated for C15H29N3O3 299.22, found 300.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:42])[C:29]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=2)([OH:34])[C:30]([F:33])([F:32])[F:31])=[C:24]([Cl:43])[CH:23]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:42])[C:29]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=3)([OH:34])[C:30]([F:31])([F:32])[F:33])=[C:24]([Cl:43])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 18 h

Procedure:
Copper(II)acetate (60 mg), (4-methoxycarbonylphenyl)boronic acid (CAS Reg. No. 99768-12-4, 59 mg), and triethylamine (44 mg) were added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 68 step 4, 40 mg) in DCM (4 ml). The mixture was stirred with molecular sieves under air atmosphere for 18 h and then concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg) as a white foam. MS (m/e)=499.1 [M+H+].
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.S(Cl)([Cl:32])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:32][C:17]1[C:7]2[S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:9]=3[C:8]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1
Reaction time: 19 h
Yield: 88.3 %

Procedure:
To a solution of methanesulfonic acid 4-benzo[b]naphtho[2,3-d]thiophen-11-yl-phenyl ester (1.00 g, 2.47 mmol) in chloroform (10 mL) was added sulfuryl chloride (0.21 mL, 2.60 mmol, 1.05 eq) dropwise at room temperature under a dry nitrogen atmosphere. After stirring 19 hours the reaction mixture was added to water (100 mL) and the organics were extracted with ether (2×100 mL). The extracts were combined, washed with brine, combined with silica gel and the solvent was removed. The adsorbate was flash chromatrographed (85/15 petroleum ether/ethyl acetate) to give the title compound as a white solid (0.957 g, 88%): mp 155-158° C.; NMR (CDCl3); δ 8.41 (ddd, J=8, 1, 1 Hz, 1H), 7.82 (ddd, J=8, 1, 1 Hz, 1H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.61-7.56 (m, 3H), 7.51-7.45 (m, 3H), 7.42-7.38 (ddd, J=8, 7, 1 Hz, 1H), 7.10 (ddd, J=8, 7, 1 Hz, 1H), 6.64 (d, J=8 Hz, 1H), 3.34 (s, 3H); MS (+EI) : [M+], 1 chlorine isotope pattern, 438 (100%), 440 (40%); Anal. Calc. for C23H15ClO3S2: C, 62.93, H, 3.49, N, 0.00. Found: C, 62.72, H, 3.25, N, 0.03.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[CH:6]2.C([O-])([O-])=O.[Na+].[Na+].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=1
Reactant: O=c1ccc2cc(C(F)(F)F)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
6-(trifluoromethyl)-1,2-dihydroquinolin-2-one (1.0 g, 4.7 mmol) was dissolved in POCl3 (15 ml) and stirred for 2 h at 110° C. (oil bath). The resulting mixture was dissolved in ice-water (100 ml) and adjusted pH to 8 with aqueous Na2CO3 solution (3N). The crude product was then extracted with dichloromethane (3×80 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford 2-chloro-6-(trifluoromethyl)quinoline as a dark red solid (944 mg, 87%). (ES, m/z): [M+H]+ 232. 1H NMR (300 MHz, DMSO): δ 8.59-8.66 (m, 2H), 8.01-8.17 (m, 2H), 7.75 (d, J=8.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH3:5].CN(C)C=O.[Cl:21][CH2:22][C:23](Cl)=[O:24].Cl>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]([N:6]([C:23](=[O:24])[CH2:22][Cl:21])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH3:5])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C(C)Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C)N(C(=O)CCl)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
18.4 g of α-(2,6-dichloroanilino)-propionic acid methyl ester, 1 ml of dimethylformamide and 100 ml of chlorobenzene are heated to 100° (internal temperature). An addition is made dropwise at this temperature, with stirring, of 8 ml of chloroacetyl chloride. After the evolution of HCl has ceased, stirring is maintained for 1 hour at 130°-140° bath temperature. The reaction mixture is allowed to cool to room temperature, the solvent is removed in a rotary evaporator, and the yellow oil remaining as residue is crystallised from diisopropyl ether. There is obtained 16 g of final product having a melting point of 82°-85° (Compound No. 10).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][C@@H:27]([NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][N:22]=1)[CH3:30]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: C[C@@H](CO)Nc1ncc(N)cn1
Product: C[C@@H](CO)Nc1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-2-hydroxy-1-methyl-ethylamino)-pyrimidin-5-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-2-(5-amino-pyrimidin-2-ylamino)-propan-1-ol. LCMS calcd for C18H16F3N5O3 (m/e) 407, obsd 408 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:25][CH2:26][CH3:27])[CH3:24].[ClH:28]>CN(C=O)C.CO>[ClH:28].[O:25]([C:26]1[CH:2]=[CH:3][CH:4]=[CH:5][C:27]=1/[CH:12]=[CH:13]\[CH2:14][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1)[C:23]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:24]=1
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1C1CCN(C/C=C\c2ccccc2Oc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0 M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:23]3[CH2:31][C:30]4[C:25](=[C:26]([N+:32]([O-])=O)[CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:35])[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[C:24](=[O:35])[N:23]([CH:16]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:14])[F:15])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:7]=1)[CH2:17][C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH2:31]2
Reactant: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc(N)c2C1=O
Yield: 97.4 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N,N-dimethyl-propionamide (330 mg, 0.67 mmol) in ethyl acetate (100 ml) was added 10% Pd on carbon (100 mg). The suspension was shaked under about 50 psi hydrogen atmosphere at room temperature overnight. The suspension was filtered through a pad of celite. The solvent was removed and the resulted oil was purified by HPLC (CH3CN:water=40:60) to give 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (300 mg, 65%): mp 70-72° C.; 1H NMR (CDCl3): δ 0.31-0.37 (m, 2H), 0.58-0.65 (m, 2H), 1.21-1.28 (m, 1H), 2.90 (s, 3H), 3.05 (dd, J=6.3, 15.8 Hz, 1H), 3.09 (s, 3H), 3.52 (dd, J=8.5,15.3 Hz, 1H), 3.85 (d, J=7 Hz, 2H), 4.20 (d, J=16.8 Hz, 1H), 4.35 (d, J=16.8 Hz, 1H), 5.20 (broad, 2H), 5.56 (dd, J=6.3, 8.5 Hz, 1H), 6.52-6.63 (m, 2H), 6.59 (t, JH-F=75 Hz, 1H), 6.90-6.98 (m, 1H), 7.09-7.26 (m, 3H); 13C NMR (CDCl3): δ 10.8, 36.2, 37.0, 38.1, 49.8, 54.3, 114.0, 114.9, 116.3, 116.9, 120.1, 121.0, 123.3, 133.4, 139.4, 140.5, 143.4, 146.6, 151.3, 170.4, 170.9; Anal. Calcd. for C24H27F2N3O4+0.18H2O: C, 62.30; H, 5.96; N, 9.08; H2O, 0.7; Found: C, 62.30; H, 5.89; N, 9.02; H2O, 0.7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Solvent: CCO
Product: COC(=O)c1c(Oc2ccc(Cl)cc2[N+](=O)[O-])c2ccccc2n1Cc1ccccc1

Procedure:
In the same way as described in example 5, methyl-3-[2-nitro-4-chlorophenoxy]-indole-2-carboxylate was alkylated with benzyl bromide. Analytical material was obtained by recrystallization from ethanol, mp. 120°-1°.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:24]=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([O:19]CC)=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[C:5]=1[N:25]1[CH2:30][CH2:29][C:28]([OH:41])([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:27][CH2:26]1>C(O)C.O>[F:3][C:4]1[CH:24]=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([OH:19])=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[C:5]=1[N:25]1[CH2:30][CH2:29][C:28]([OH:41])([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cn(C)c2cnc3c(N4CCC(O)(c5cccc(C(F)(F)F)c5)CC4)c(F)ccc3c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2c3ccc(F)c(N4CCC(O)(c5cccc(C(F)(F)F)c5)CC4)c3ncc21
Temperature: 80 °C
Yield: 50.4 %

Procedure:
1.02 cm3 of 1 N aqueous potassium hydroxide was added, with stirring, to a suspension of 0.46 g of ethyl 8-fluoro-7-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 5 cm3 of ethanol and 4 cm3 of water. The mixture was heated at about 80° C. for 2 hours and then evaporated to dryness. The residue was dissolved in 20 cm3 of water, the aqueous phase was washed with 20 cm3 of dichloromethane, acidified with 0.06 cm3 of acetic acid and then extracted 3 times with 50 cm3 of dichloromethane. The organic phase was dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa). The residue obtained was washed twice with 5 cm3 of diisopropyl ether and dried. 0.22 g of 8-fluoro-7-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of a yellow solid, which melted at 245° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH2:16])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2].C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3N)[nH]c2cc1CC
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)[nH]c2cc1CC
Reaction time: 48 h
Yield: 83.9 %

Procedure:
A solution of 3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine [0.3 g, Reference Example 49(a)] and triethylamine (0.8 mL, excess) in tetrahydrofuran (20 mL) was treated dropwise with cyclopropanecarbonyl chloride (0.3 g, 2.4 mmol). This mixture was stirred for 48 hours then diluted with aqueous sodium bicarbonate solution (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was dissolved in tetrahydrofuran (50 mL). This solution was treated with a solution of potassium hydroxide (1.1 g) in ethanol (10 mL) and the mixture was stirred for 2 hours, then poured into water (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1/1, v/v) to give cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide (0.3 g) as an off-white solid. LC-MS (Method E): RT 2.99 minutes, 424 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH3:9][S:10]([CH3:13])(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(C)(=O)=O
Reactant: Fc1cc(Br)ccn1
Product: CS(=O)(=O)Cc1cc(Br)ccn1
Yield: 91 %

Procedure:
The title compound was prepared from 4-bromo-2-fluoro-pyridine and dimethylsulfone following a procedure analogous to that described in Step 1 for Intermediate 14. Yield: ca. 91% of theory (crude); LC (method 3): tR=2.01 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.