Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.[F-].[Cs+].C(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3[C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)cc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.112 g, 0.209 mmol), pyridine-3-boronic acid (0.077 g, 0.626 mmol), and cesium fluoride (0.111 g, 0.731 mmol) in dry ACN (7 mL) is purged with N2 and then treated with 1,1′-bis(diphenylphophino)-ferrocene palladium (II) chloride complex with DCM (0.031 g, 0.042 mmol). The mixture is heated to 100° C. and stirred for 5 hours under N2. The reaction is cooled, and the crude mixture is absorbed on silica gel and purified by flash chromatography using 2/1 hexanes/ethyl acetate to afford 0.089 g (79%) of the title compound. Rf=0.33 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H28O4NF3 535, found 536 (M+1, 100%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[C@@H:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCCc1ccccc1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](CCc1ccccc1)CC(=O)OC(C)(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxo-4-phenylbutyl)-2-oxazolidinone (8.83 g), prepared in Referential Example 91, and tert-butyl bromoacetate (25.0 ml), there was obtained the desired compound (7.35 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:15]2[O:14][C:13]3[CH:16]=[CH:17][C:18]([C:22](=[CH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:19]([O:20][CH3:21])[C:12]=3[C:11](=[O:28])[O:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH3:29])[CH:5]=1)[CH3:2].[OH-:30].[Na+].OO>CCCCCC.O1CCCC1.C(O)C>[CH2:1]([O:3][C:4]1[C:15]2[O:14][C:13]3[CH:16]=[CH:17][C:18]([CH:22]([CH2:27][OH:30])[CH2:23][CH:24]([CH3:25])[CH3:26])=[C:19]([O:20][CH3:21])[C:12]=3[C:11](=[O:28])[O:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH3:29])[CH:5]=1)[CH3:2]
Reactant: C=C(CC(C)C)c1ccc2c(c1OC)C(=O)OCc1cc(C)cc(OCC)c1O2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: CCOc1cc(C)cc2c1Oc1ccc(C(CO)CC(C)C)c(OC)c1C(=O)OC2
Reaction time: 14 h

Procedure:
2 ml (1 mmol) of a 0.5 M 9-borabicyclo-3.3.1-nonane solution in hexane are added dropwise under argon to a solution of 130 mg (0.33 mmol) of the compound from Example 148 in 4 ml of absolute tetrahydrofuran. After 14 h at room temperature, a few drops of ethanol, 2 ml of 2 N sodium hydroxide solution and 0.5 ml of 30% strength hydrogen peroxide solution are added. The mixture is stirred vigorously for 3 h and then concentrated carefully and the residue is taken up in dichloromethane. The solution is washed with water, and the organic phase is dried over magnesium sulphate and concentrated, and the residue is purified by column chromatography on silica gel using petroleum ether/ethyl acetate 6:1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][C:62]1[C:66]([NH2:67])=[CH:65][O:64][N:63]=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:67][C:66]1[C:62]([CH3:61])=[N:63][O:64][CH:65]=1)=[O:9]
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1NC(=O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and 3-methyl-4-isoxazolamine (26.8 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 65 mg.
Reaction SMILES: [NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@:5]([Si](C(C)(C)C)(C)C)([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1>C1COCC1>[NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1
Reactant: Cc1cn([C@@]2([Si](C)(C)C(C)(C)C)C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 72 %

Procedure:
3'-O-Amino-(t-butyldimethylsilyl)thymidine was deblocked with (Bu)4 NF/THF in standard way to furnish compound 4 (72%). Crystallized from ether/hexanes/ethanol as fine needles, mp 81° C. 1H NMR (Me2SO--d6) δ1.78 (s, 3, CH3), 2.17 and 2.45 (2 m, 2, 2'CH2), 3.70 (m, 2, 5'CH2), 3.88 (m, 1, 4'H), 4.16 (m, 1, 3'H), 4.8 (br s, 1, 5'OH), 6.05 (dd, 1, 1'H), 6.2 (br s, 2 NH2), 7.48 (s, 1, C6H), and 11.24 (br s, 1, NH). Anal. Calcd. for C10 H15N3O5 : C, 46.69; H, 5.87; N, 16.33; found: C, 46.55; H, 5.91; N, 16.21.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>CN(C)C(=O)C.O.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>[CH3:20][N:18]1[CH:19]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[C:33]=4[F:34])=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Reactant: OB(O)c1cccc(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(CN2CCN(c3nccnc3-c3cccc(F)c3F)CC2)cn1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
Dissolve 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (160 mg, 0.55 mmol) in N,N-dimethylacetamide (4 mL) and water (2 mL) and purge with nitrogen for 0.5 hr. Add potassium carbonate (180 mg, 1.30 mmol) then 2,3-difluorobenzeneboronic acid (100 mg, 0.66 mmol) and purge with nitrogen for 0.5 hr. Add tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.0086 mmol) and heat at 110° C. for 3.25 hr. Cool to room temperature and purify (silica gel chromatography, eluting with 0:100 to 30:70 methanol:DCM), followed by reverse phase HPLC to give the title compound (52.69 mg, 26%). MS (ES): m/z=371 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10](=[O:14])[CH:11]([CH3:13])[CH3:12]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccc(Br)cc1
Reactant: CC(C)C=O
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(Br)cc1

Procedure:
A solution of 4-bromophenylmagnesium bromide in ether was treated with isobutyraldehyde to give 1-(4-bromophenyl)-2-methylpropan-1-ol, b.p. 152°-154°C./15mm. This was dehydrated with polyphosphoric acid at 20°C., to give 1-bromo-4-(2-methyl-1-propenyl)benzene, b.p. 110°-112°C./6mm, which was hydrogenated in an ether/ethanol solvent containing 50% hydrobromic acid (2% by volume of solvent) over platinum oxide to give the desired product, b.p. 120°-122°C./22mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH:39]([O:38][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:27][CH2:26]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottom flask was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (80 mg, 0.2 mmol) and triethylamine (200 μl). DMF (3 mL) was added to completely dissolve the solid material. The reaction flask was immersed in an ice-bath. Isopropyl chloroformate (1.0M in toluene, 0.22 mL) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC to give 4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound A129). 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H), 1.9 (m, 2H), 2.12 (m, 2H), 3.13 (s, 3H), 3.40 (m, 2H), 3.91 (m, 2H), 4.97 (m, 1H), 5.63 (m, 1H), 7.95 (m, 3H), 8.34 (s, 1H), 8.63 (s, 1H). Exact mass calculated for C21H24FN5O5S: 477.15, found 478.2 (MH+).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=[O:10])[CH2:6][CH:7]([CH3:9])[CH3:8].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[OH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: CCC=O
Reactant: CC(C)CC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O)[C@H](C)C=O
Reaction time: 16 h
Yield: 88 %

Procedure:
A solution of freshly distilled propionaldehyde (144 μL, 2.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 2.5 h to a stirring suspension of isovaleraldehyde (107 μL, 1.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at 4° C. After 16 h, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions of dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 88% yield (126 mg, 0.88 mmol), 97% ee and 3:1 anti:syn. IR (film) 3419, 2958, 2935, 2872, 1719,1466, 1368, 1152, 1098, 1062,1025, 976.5 cm−1; 1H NMR (300 MHz, CDCl3) δ9.75 (d, J=1.5 Hz, 1H, CHO); 3.89 (ddd, 1H, J=9.9, 6.6, 2.7 Hz, 1H, CHOH); 2.44 (m, 1H, CHCH3); 1.83 (m, 1H, CH(CH3)2); 1.47 (m, 1H, CH2); 1.26 (m, 1H, CH2); 1.14 (d, 3H, J=7.2 Hz, CH3CHCHO); 0.97 (d, 3H, J=5.1 Hz, (CH3)2CH); 0.92 (d, 3H, J=6.6 Hz, (CH3)2CH); 13C NMR (75 MHz, CDCl3) δ205.5, 70.9, 52.8, 44.0, 34.5, 24.1, 21.8, 11.1; HRMS (CI) exact mass calcd for [M +H]+ (C8H17O2) requires m/z 145.1228, found m/z 145.1225; [α]D=−33.6 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the acetal derived from 2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto, supra) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (100° C. isotherm, 23 psi); (2S, 3S) anti isomer tr=50.8 min, (2R, 3R) anti isomer tr=53.2 min, (2R, 3S) and (2S, 3R) syn isomers tr=45.5 min.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)cc3[nH]c4ncc(C)cc4c23)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)N3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 3 h
Yield: 67.1 %

Procedure:
Compound 139 (40 mg, 0.1 mmol) and HOBT (17 mg, 0.11 mmol) stirred in CH2Cl2 (2 mL) at r.t. EDC (29 mt, 0.15 mmol) and 1-methylpiperazine (45 mL, 0.4 mmol) were added, and the reaction stirred for 3 h. Organics were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by prep-HPLC gave 32 mg (67%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.22 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6 Hz), 7.87-7.95 (m, 2H), 7.80 (s, 1H), 7.40 (s, 1H), 3.39-3.62 (m, 4H), 3.31 (q, 2H, J=7.2 Hz), 3.16-3.30 (m, 4H), 2.95 (s, 3H), 2.38 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C26H28N4O3S, 477; found 477.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[C:33]([F:35])[CH:34]=2)[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]([CH3:57])[CH3:56])(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][C:33]=2[F:35])[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2cc(F)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C(C)C)ccc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C(C)C)c(c1)CN(C)C(=O)[C@@H]2Nc1cc(F)c2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 17.4 %

Procedure:
A solution of 20E (123 mg, 0.149 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.081 mL, 0.164 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.208 mL, 1.489 mmol) in CH2Cl2 (260 mL) at rt. The solution was stirred at rt for 16 h. The solvent was concentrated and the crude product was purified by flash chromatography to give a mixture of diastereoisomers (60 mg, 47.3% yield). The diastereoisomers were separated by a prep chiral HPLC to give 20F (22 mg, 0.026 mmol, 37.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][CH:5](SC)[C:6]([NH2:8])=[O:7].Cl[C:30]1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][CH:5]([S:45]([CH3:30])(=[O:49])=[O:47])[C:6]([NH2:8])=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CSC(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(C(N)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(methylthio)acetamide and 50 ml of chloroform, 3.7 g of m-chloroperbenzoic acid were added and stirred at room temperature for 3 days. To the reaction mixture, aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution were added. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to give 3.3 g of 2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(methylsulfonyl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[S:21][C:5]2[CH2:6][N:7]([C:10]([C:12]3[CH:20]=[CH:19][C:15]4[NH:16][N:17]=[N:18][C:14]=4[CH:13]=3)=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>N1C=CC=CC=1.CS(C)=O>[NH:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:10]([N:7]3[CH2:8][CH2:9][C:4]4[C:3]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[C:2]([NH:1][C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=5)=[O:38])[S:21][C:5]=4[CH2:6]3)=[O:11])=[CH:13][C:14]=2[N:18]=[N:17]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 4 %

Procedure:
Starting material 13 (1.2 g, 20% content, 0.6 mmol) was dissolved in 5 ml pyridine and one half of 112 mg (0.7 mmol) p-chlorphenyl isocyanate was added. The reaction mixture was stirred over night at ambient temperature. Then the other half of the p-chlorphenyl isocyanate was added and the reaction was again stirred over night at ambient temperature. The reaction was now concentrated in vacuo and the thereby isolated crude product was dissolved in 7 ml DMSO and purified by prep. HPLC (Method 3). The pure fractions were combined, the solvent reduced and the product finally lyophilized. The desired product 14 could thereby be isolated as yellow solid (16.2 mg, 4%; and additional 17 mg, 84% content 14, 4% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:29](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 30 mg, 0.1 mmol), picolinic acid (15 mg, 0.12 mmol), and HATU (46 mg, 0.12 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.3 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 70% acetonitrile/water to yield the final product as a yellowish solid (35 mg, 86% yield). MS (apci) m/z=403.2 (M+H).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.C(N(CC)CC)C.[C:23]1([C:29]2[O:33][C:32]([C:34]([N:36]3[CH2:39][CH:38]([O:40][C:41]4[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=4)[CH2:37]3)=[O:35])=[N:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:45][C:44]2[CH:43]=[CH:42][C:41]([O:40][CH:38]3[CH2:37][N:36]([C:34]([C:32]4[O:33][C:29]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[N:30][N:31]=4)=[O:35])[CH2:39]3)=[CH:48][CH:47]=2)[CH2:8][O:9]1
Reactant: C1CNC2(C1)COC2
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CCCC34COC4)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.16 g, 67%, 0.47 mmol) was dissolved in dichloromethane (3 ml). Triethyl amine (0.119 ml, 0.86 mmol) was added, followed by 4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.15 g, 0.43 mmol) and finally sodium triacetoxyhydroborate (0.182 g, 0.86 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) was added and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a colourless residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.140 g (73%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62 (dt, 2H), 2.09-2.15 (m, 2H), 2.47-2.5 (m, 2H), 3.90 (d, 2H), 4.08-4.14 (m, 1H), 4.43 (d, 2H), 4.54-4.59 (min, 1H), 4.64 (ddd, 1H), 4.80 (d, 2H), 5.09-5.13 (m, 1H), 5.16 (ddd, 1H), 6.87 (d, 2H), 7.30 (d, 2H), 7.64-7.74 (m, 3H), 8.07-8.13 (m, 2H). MS (APCI+) m/z 447.2 [M+H]+, LC purity: 94%.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[N:12]1([CH2:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:32][C:16]1[C:15]2[N:14]=[CH:13][N:12]([CH2:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CNC(=O)CCn1cnc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CNC(=O)CCn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCPBA (8.95 g, 38.9 mmol) was added to a solution of 3-(1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide (4.4 g, 15.6 mmol) in chloroform (100 mL); the reaction was stirred for one hour at ambient temperature. Ammonium hydroxide (40 mL) was added, and the mixture was stirred vigorously for 15 minutes. p-Toluenesulfonyl chloride (5.94 g, 31.2 mmol) was added over a period of ten minutes, and the reaction was stirred for two hours. The reaction mixture was filtered to remove a precipitate, and the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from methanol to provide 0.535 g of 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide as off-white needles, mp>260° C.