Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Na].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].Cl[CH2:16][P:17](=[O:20])([CH3:19])[CH3:18]>>[CH3:16][P:17]([CH3:18])([N:9]1[C:8]2[C:7](=[O:13])[N:6]([CH2:16][P:17](=[O:20])([CH3:19])[CH3:18])[C:5](=[O:14])[N:4]([CH3:3])[C:12]=2[N:11]=[CH:10]1)=[O:20]
Reactant: CP(C)(=O)CCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na]
Product: Cn1c(=O)n(CP(C)(C)=O)c(=O)c2c1ncn2P(C)(C)=O

Procedure:
The title substance was prepared from 22 g (0.1 mol) of 3-methylxanthine disodium salt and chloromethyldimethylphosphine oxide analogously to Example 59 and crystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.[NH2:38][CH2:39][CH2:40][C:41]#[N:42].[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:28][CH2:29][CH:30]([NH:42][CH2:41][CH2:40][C:39]#[N:38])[CH2:31][CH2:32]3)[N:9]=2)[CH:7]=1
Reactant: O=C1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: N#CCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#CCCNC1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Yield: 2 %

Procedure:
To solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-oxocyclohexylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (300.0 mg, 0.569 mmol) in methanol (30 mL) was added 3-aminopropanenitrile (199.5 mg, 2.85 mmol). The resulting solution was stirred at room temperature for 3. Then NaBH3CN (71.56 mg, 1.14 mmol) was added. The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was applied onto a short pad of silica gel eluting with ethyl acetate. The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/0.05% NH4HCO3=30% increasing to ACN/0.05% NH4HCO3=55% within 8 min; Detector, UV 254 nm. 6.7 mg product was obtained. This resulted in 6.7 mg (2%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a off-white solid. LCMS (Method 34) [M+H]+=581.4, RT=2.44 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.68-8.66 (m, 2H), 8.27 (s, 1H), 7.64-7.60 (m, 2H), 7.43 (d, 1H, J=8.1 Hz), 7.27 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.5 Hz), 5.45 (t, 1H, J=6.9 Hz), 4.80 (d, 2H, J=7.2 Hz), 2.79-2.72 (m, 3H), 2.71-2.57 (m, 5H), 2.10-1.97 (m, 2H), 1.94-1.86 (m, 2H), 1.23-1.16 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]12[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9][CH2:10]1)[C:6](=[O:7])[C:4]2=[O:5].[C:14]([C:18]1[CH:23]=C(C)C=C(C(C)(C)C)[C:19]=1[OH:29])(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)=C>O1CCOCC1>[C:19]([O:1][CH2:2][C:3]12[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9][CH2:10]1)[C:6](=[O:7])[C:4]2=[O:5])(=[O:29])[C:18]([CH3:23])=[CH2:14]
Reactant: CC1(C)C2CCC1(CO)C(=O)C2=O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC12CCC(C(=O)C1=O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Analogously to L. Angiolini et al., 2000, Macromol. Chem. Phys. 201, 2646, a mixture of 10 mmol (1.82 g) of 10-hydroxycamphorquinone, 10 mg of 2,6-di-tert.butyl-4-methylphenol (inhibitor), 1.5 ml of dry triethylamine (TEA) and 50 ml of absolute 1,4-dioxane, under argon and with exclusion of daylight, was added dropwise at 0° C. to a stirred solution of 11 mmol (1.15 g) of methacrylic acid chloride, dissolved in 20 ml of 1,4-dioxane. There followed stirring for 2 h at room temperature and 2 h under reflux. The reaction mixture was filtered off from the formed TEA-HCl, diluted with diethyl ether, washed with 5% sodium bicarbonate solution and with water. After drying over anhydrous Na2SO4 the solution was concentrated to dryness in a rotary evaporator and the solid crude product recrystallized from toluene/n-hexane (20:80 v/v). 1.55 g (62% of the theory) of yellow crystals of 10-methacryloyloxycamphorquinone MACQ was obtained.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]B(O)O)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].OO.CO>C1COCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[N:16][CH:17]=1
Reactant: CCCCCCCCc1ccc(-c2ccc(OB(O)O)cn2)cc1
Agent: OO
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2ccc(O)cn2)cc1
Reaction time: 8 h
Yield: 67 %

Procedure:
2-(4-Octylphenyl)pyridin-5-yl-boric acid (10 g) was mixed with 20 ml of aqueous hydrogen peroxide (36%), methanol (80 ml) and THF (80 ml) to stand overnight under gentle agitation at room temperature. Organic matter in the reaction mixture was extracted by diethyl ether (200 ml), followed by washing the extract sequentially with saturated aqueous sodium hydrogen sulfite, distilled water and aqueous ammonium chloride to be dried over MgSO4. This extract mixture was concentrated by distilling off the solvent to obtain solid product, which was purified by recrystallization from mixed solvent of heptane and ethyl acetate to give 5-hydroxy-2-(4-octylphenyl)pyridine (5.8 g). The melting point of this product was found to be 134-135.5° C.
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)(=O)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CN(C)C=O>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: C1COCCN1
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCN4CCOCC4)c(F)c3)cc(=O)c12
Reaction time: 1.5 h

Procedure:
500 mg (1.07 mmol) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 52 was dissolved in 15 ml of dimethylformamide, 0.93 ml of morpholine was added and the mixture was stirred at 50° to 60° C. for 1.5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine =200:10:1) and recrystallized from ethyl acetate/n-hexane to give Compound 55 which was converted into hydrochloride according to the same manner as that in Example 16 to give 349 mg (62%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-ethoxyphenylboronic acid (Aldrich, Buchs, Switzerland, 21.4 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: tR 2.84 min (Method A); M+H=414 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.16 (s, 1H), 8.09-8.06 (m, 1H), 7.94-7.91 (m, 1H), 7.57-7.59 (m, 1H), 7.39-7.35 (m, 1H), 7.12-6.92 (m, 3H), 4.09 (q, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.37 (t, 3H))
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:13](=O)[CH2:12][N:11]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(COCC2C=CC(OC)=CC=2)C(O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.[CH2:69]([O:72][NH:73][S:74]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[N+:83]([O-:85])=[O:84])(=[O:76])=[O:75])[CH:70]=[CH2:71].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:69]([O:72][N:73]([CH:13]1[CH2:12][N:11]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:15]=[C:14]1[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[S:74]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[N+:83]([O-:85])=[O:84])(=[O:76])=[O:75])[CH:70]=[CH2:71]
Reactant: COc1ccc(COCC2=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC2=O)cc1
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: COc1ccc(COCC2=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COCc1ccc(OC)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (S)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((4-methoxybenzyl)-oxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 169, 17.10 g, 34.78 mmol) and N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 9.88 g, 38.26 mmol) according to the procedure described for Intermediate 10. Desired product was obtained as a pale yellow oil, 18.70 g, 74%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)([CH3:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)([CH3:13])[CH3:12])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc2ncccc2c1
Agent: [Na+]
Product: CC(C)(N=[N+]=[N-])c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
2-(Quinolin-6-yl)propan-2-ol (0.50 g, 2.67 mmol) and sodium azide (1.73 g, 26.70 mmol) were added successively to ice-cold trifluoroacetic acid (20 ml) and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with water and basified with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as brown liquid (0.340 g, 60%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.90 (dd J=4.1, 1.6 Hz, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.88 (dd, J=8.1, 2.2 Hz, 1H), 7.56 (q, J=4.2 Hz, 1H), 1.71 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH2:30][N:31]2[C@H:35]([CH3:36])[C@H:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:33][C:32]2=[O:43])[CH:6]=1.[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1>>[CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:49]2[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=2)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][C:21]=2[CH2:30][N:31]2[C@H:35]([CH3:36])[C@H:34]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:33][C:32]2=[O:43])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COC(=O)Cc1ccc(-c2cnn(C)c2)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12].[Cl-].[NH4+]>O1CCCC1>[CH2:10]([C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[Mg]Br
Reactant: OCc1cccnc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)Cc1ncccc1CO
Reaction time: 4 h

Procedure:
To a solution of (2-bromopyridin-3-yl)methanol (100 mg) in tetrahydrofuran (1 ml), 36 mg of dichloro(1,1′-bis(diphenylphosphino)ferrocene)nickel(II) and 0.8 ml of isobutyl magnesium bromide (2.0M diethyl ether solution) were added under ice-cooling, and the reaction solution was stirred at the same temperature for 4 hours. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50:50)) to afford the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:19][CH:20]=2)=[CH:9][C:8]=1[CH2:27][O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)C.[OH-].[Na+]>C(O)C>[CH:31]1([NH:30][C:29]([O:28][CH2:27][C:8]2[CH:9]=[C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[O:19][CH:20]=3)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCCC1
Temperature: 55 °C
Yield: 69.3 %

Procedure:
To a 15 mL round bottom flask were charged 0.10 g (0.17 mmol) of 3-{2-cyclohexylcarbamoyloxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid ethyl ester dissolved in 2 mL of ethanol. Next this solution was treated with 0.48 mL (0.96 mmol) of 2N NaOH and then heated to 55° C. for 2 h. The volatiles were removed in vacuo and this crude residue was taken up in 20 mL of EtOAc and 10 mL brine and acidified with 1 mL of 5N HCl. The aqueous layer was discarded and the organic layer was dried over Na2SO4 and removed in vacuo. The crude residue was submitted for mass-directed HPLC purification to give a white solid (0.058 g, 63%). MS (ES) m/e 537 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[CH:29]=[C:28]([O:30]CC2C=CC(OC)=CC=2)[N:27]=[C:26]([NH:40][C@@H:41]2[CH2:46][CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]2)[N:25]=1.C(O)(C(F)(F)F)=O>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[N:25]=[C:26]([NH:40][C@@H:41]2[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]2)[N:27]=[C:28]([OH:30])[CH:29]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(-c2n[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCNC2)n1
Temperature: 120 °C
Yield: 64 %

Procedure:
A glass microwave reaction vessel was charged with (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-6-(4-methoxybenzyloxy)pyrimidin-2-ylamino)piperidine-1-carboxylate (145 mg, 0.200 mmol) and TFA (1.5 mL, 19.47 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. then solvent was removed. The residue was purified with preparative HPLC (10-50% ACN in water with 0.1% TFA) to give (R)-6-(5-(2,6-difluorophenyl)-1H-indazol-3-yl)-2-(piperidin-3-ylamino)pyrimidin-4-ol (54.0 mg, 0.128 mmol, 64.1% yield) as a TFA salt. MS (ESI, pos. ion) m/z: 423 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 13.65 (1 H, br. s.), 8.59-8.71 (1 H, m), 8.41-8.56 (2 H, m), 7.73 (1 H, s), 7.41-7.55 (2 H, m), 7.17-7.32 (2 H, m), 6.87 (1 H, br. s.), 6.40 (1 H, br. s.), 4.18 (2 H, br. s.), 3.23 (1 H, d, J=10.4 Hz), 3.01-3.16 (2 H, m), 2.87 (1 H, q, J=10.0 Hz), 2.11 (1 H, d, J=13.1 Hz), 1.70-1.84 (1 H, m), 1.38-1.65 (2 H, m).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][CH:24]1[CH:29]([OH:30])[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][CH:29]([OH:30])[CH:24]([CH2:23][NH2:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NCC1CNCCC1O
Product: Cc1c(F)c(N2CCC(O)C(CN)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 45.9 %

Procedure:
The condensation of 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-aminomethyl-4-hydroxy-piperidine was carried out in a similar manner as described in example 1 gave the titled product. Yield 45.9%, m.p 270–75° C., C20H23F2N3O4, m/z 408 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>N1C=CC=CC=1>[CH2:9]([O:8][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)O1
Reactant: N#CCCCCNOCc1ccccc1
Solvent: c1ccncc1
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
N-Benzyloxy-N-(4-cyanobutyl)succinamic acid (6) was synthesized by charging a flask with 2.8 g (13.7 mmol) of (5) in 23 mL of pyridine and 2.1 g (20.8 mmol) of succinic anhydride, heated at 100° C. for 1.5 hours and then allowed to cool to room temperature and to stir overnight. The pyridine was removed under vacuum and the residue was dissolved in a is minimal amount of chloroform and filtered. The chloroform was removed and the residue was dissolved in ether, which was extracted three times with 20% potassium bicarbonate (3×50 mL). The aqueous solutions were combined, acidified and extracted with ether. This solution was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was then chromatographed on 70-230 mesh silica gel by eluting with 5% methanol in chloroform to give 4.12 g (98%) of (6): NMR δ 1.56-1.7 (m, 2 H), 1.7-1.97 (m, 2 H), 2.36 (to 2 H), 2.60-2.80 (m, 4 H); 3.68 (t, 2 H), 4.85 (s, 2 H), 7.4 (s, 5 H); IR (CHCl3) 3670, 2930, 2240, 1710, 1650, 1415, 1200 cm-1. Anal. calcd. for C16H20N2O4 : C, 63.17; H, 6.64. Found: C, 63.36; H, 6.74. A sample of (6) was crystallized from hexane/EtoAc, mp 71° C.
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:22](=[O:31])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:11]=[N:12][CH:13]=1.[NH:32]([CH2:35][CH3:36])[CH2:33][CH3:34]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]2[C:22](=[O:31])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:9]=2)=[CH:25][CH:26]=1
Reactant: O=c1c2ccccc2nc(-c2cncc(Br)c2)n1-c1ccc(Cl)cc1
Reactant: CCNCC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCN(CC)c1cncc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)c1
Yield: 10 %

Procedure:
Pd(OAc)2 (0.031 g, 0.14 mmol), DPPF (0.066 g, 0.12 mmol), and NaOtBu (0.059 g, 0.62 mmol) were added to a mixture of 2-(5-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one (0.200 g, 0.48 mmol) and Et2NH (0.07 mL) in toluene (2 mL). The reaction mixture was microwaved at 90° C. and 300 W (max. power) with cooling for 3 hours, before concentration in vacuo. Purification by flash chromatography on silica gel, eluting with 35% to 90% EtOAc in heptane, plus further purification by reverse-phase chromatography, eluting with 10% to 50% CH3CN in H2O, afforded the title compound as a white solid (0.02 g, 10%). 1H-NMR (300 MHz, DMSO-d6): δ8.21 (d, J=6.6 Hz, 1H), 7.88-8.02 (m, 2H), 7.73-7.87 (m, 2H), 7.57-7.70 (m, 1H), 7.36-7.50 (m, 4H), 6.89 (s, 1H), 3.16-3.29 (m, 4H), 0.72-1.11 (m, 6H). MS (APCI) m/z: 405 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]1([C:10]2[S:14][C:13]([N:15]=[C:16]=[O:17])=[N:12][N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.NN>C(Cl)Cl>[CH3:1][N:2]([C:16]([NH:15][C:13]1[S:14][C:10]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:11][N:12]=1)=[O:17])[NH2:3]
Reactant: CNN
Reactant: O=C=Nc1nnc(C2CCCCC2)s1
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C2CCCCC2)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: C([O-])(O)=[O:2].[Na+].[OH:6][CH2:7][CH:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.[Na+].[Br-].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1.CC(O)C>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][O:13][CH:8]([C:7]([OH:2])=[O:6])[CH2:9]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reaction time: 8 h

Procedure:
Saturated aqueous NaHCO3 (15 mL) was added to a stirred solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1.09 g, 5.0 mmol) (heterocycles, (1993), 35, 105 and WO 2007/06715) in acetone (50 mL) at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added for 20 min at 0° C. After addition the reaction mixture was allowed to rise to RT and stirred overnight. 2-Propanol (3 mL) was added and the resulting solution was stirred at RT for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL), acidified with 6N HCl and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to give the title compound as a white solid (1.1 g crude) (M−H) 230.