Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([N:25]=[CH:26][N:27]=4)[C:17]([C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]OCC1.BrC1N2N=CN=C2C(NC2C=CC(N3CC[NH:48][CH2:47][C:46]3=[O:51])=CC=2)=NC=1.CC([O-])(C)C.[Na+]>CN(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>[NH:22]1[CH:21]=[C:20]([C:17]2[N:16]3[N:25]=[CH:26][N:27]=[C:15]3[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][NH:48][CH2:47][C:46]4=[O:51])=[CH:8][CH:9]=3)=[N:19][CH:18]=2)[CH:24]=[N:23]1
Reactant: c1nc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n2n1
Reactant: O=C1CNCCN1c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CNCCN1c1ccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)cc1

Procedure:
This compound may be prepared using methods as described for Compound 1, step 5 using 1-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-piperazin-2-one (70 mg, 0.18 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64 mg, 0.33 mmol), Pd(PPh3)4 (21 mg, 18 μmol) and NaOtBu (70 mg, 0.72 mmol) in 2 mL of 3:1 DMF/water. The reaction mixture is concentrated under vacuum and the residue is purified by silica gel column chromatography eluting with a gradient 99:1 to 90:10 DCM:NH3 (7M in MeOH). The title compound is isolated as a pale green solid (13 mg, 19%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.05 (2H, m), 3.42 (2H, s), 3.62 (2H, m), 7.32 (2H, d), 8.07 (2H, d), 8.26 (1H, s), 8.39 (1H, br s), 8.67 (1H, br s), 8.81 (1H, s), 10.05 (1H, s), 13.32 (1H, br s). LCMS: Rt 6.98 min (92.4%), m/z (APCI) 376 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([S:36][CH2:37][CH2:38][OH:39])[CH:35]=1)[CH2:5][N:6]([CH:30]1[CH2:32][CH2:31]1)[C:7]([C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)=[O:8].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([S:36][CH2:37][CH2:38][OH:39])[CH:35]=1)[CH2:5][N:6]([CH:30]1[CH2:31][CH2:32]1)[C:7]([C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8]
Reactant: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N(Cc2cc(Br)cc(SCCO)c2)C2CC2)cc1=O
Agent: Cl
Solvent: ClCCl
Product: Cn1ccc([C@@H]2CCNC[C@H]2C(=O)N(Cc2cc(Br)cc(SCCO)c2)C2CC2)cc1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a CH2Cl2 solution (0.1 M) of trans-tert-butyl 3-{[{3-bromo-5-[(2-hydroxyethyl)thio]benzyl}(cyclopropyl)amino]carbonyl}-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-1-carboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 45 min. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 90:10 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound. MS (ESI+, M+H): 520.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:19]=[C:18]([C:20]([O:22]C)=[O:21])[CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1)[C:20]([OH:22])=[O:21]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
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: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3c2)c(F)c1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
6-Bromonaphthalen-2-ol (1 g, 4.48 mmol) was mixed with 880 mg of 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (4.48 mmol), 1.2 g of K2CO3 (9.23 mmol), 120 mg of Pd(PPh3)4 (2.5 mol %), and then suspended in 17 mL of 1,4-Dioxane and 4 mL of H2O. The mixture was degassed 3× with argon and then heated to reflux while stirring for 1 hour. 4N NaOH (5 mL) was then added and stirred at room temperature for 2 hours, back extracted with EtOAc, and filtered through Celite. The basic aqueous solution was then acidified to pH=4.3 and the solids were filtered to give about 950 mg of off-white solid. This was triturated in 8 mL DCM and 2 mL EtOAc and filtered to yield about 830 mg of off-white Example 2 (65.8% overall yield). 1H-NMR (DMSO-d6 500 MHz): δ 13.31 (bs, 1H), 9.97 (bs, 1H), 8.05 (s, 1H), 7.90 (m, 2H), 7.80 (m, 3H), 7.64 (dt, 1H), 7.19 (m, 2H); MS (ESI): m/z 281.53 [MA]−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[F:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Sn](CCCC)(CCCC)CCCC)[CH:37]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:35]=[N:34][CH:33]=[C:32]([F:31])[CH:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cncc(F)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 44.3 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), 3-fluoro-5-tributylstannanyl-pyridine (87 mg, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 3 mL of DMF was heated at 120° C. for 4 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-20% EtOAc/CH2Cl2) to give 32 mg of the title compound. MS: (+) m/z 482.30 (M+1).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:9]2[CH2:10][CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cncc(-n2ccnn2)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1c(F)c(N2CCCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 38.7 %

Procedure:
3-(1,2,3-triazol-1-yl)pyridine hydrochloride (63 mg, 0.33 mmol) and DBU (77 mg, 0.5 mmol) were added to a suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50 mg, 0.18 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 48 hrs and then concentrated under vacuo. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 30 mg of desired product. m.p. 252-254° C.; 1H NMR (TFA) δ: 9.36 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 5.28 (m, 1H), 3.60-4.66 (m, 5H), 2.10-2.58 (m, 4H), 1.32-1.68 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:31]=[C:32]([CH:42]4[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]4)[NH:33][C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:29][C:24]=2[O:23][CH2:22]1>C1COCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:31]=[C:32]([CH:42]4[CH2:47][CH2:46][CH:45]([NH:48][S:8]([CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:10])=[O:9])[CH2:44][CH2:43]4)[NH:33][C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Cc1cccc(-c2[nH]c(C3CCC(N)CC3)nc2-c2ccc3c(c2)OCO3)n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(C3CCC(NS(=O)(=O)Cc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.4 %

Procedure:
α-Toluenesulfonyl chloride (0.023 g, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 4-[4-benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl] cyclohexylamine (see Example 19; 0.038 g, 0.10 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.005 g (9%) of the title compound as a yellow solid. MS (ESP+) m/z 531.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.67 (m, 1H), 7.41 (m, 6H), 7.30 (m, 1H), 7.22 (m, 1H), 7.01 (m, 2H), 6.07 (s, 2H), 4.34 (s, 2H), 3.05 (m, 2H), 2.63 (s, 3H), 2.13 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H), 1.43 (m, 2H).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53]>C1COCC1.C1COCC1.C(OCC)(=O)C>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:46][CH2:47][CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of (4-([1,1′-biphenyl]-4-ylmethoxy)phenyl)acetic acid (2.1 g) in THF (100 ml) were added WSC (1.4 g), HOBt (1 g), and t-butyl N-(2-aminoethyl)carbamate (1 g). After stirring overnight, the reaction mixture was diluted in THF-ethyl acetate, washed with 10% aqueous potassium carbonate, dried, and concentrated. The residue was recrystallized from ethanol to obtain the titled compound (1.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2cccs2)c1
Yield: 18.6 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (310 mg, 0.87 mmol), 2-thienylboronic acid (167 mg, 1.3 mmol), 2 M Na2CO3 (3 mL) and Pd(0) (32 mg) were mixed together in toluene (6 mL), and the mixture was heated at reflux for 4 hours. The mixture was cooled and extracted with CHCl3. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 1:1 to afford the title compound (64 mg, 20% yield). MS (CINH3) m/z 287 (M+H)+. 1HH NMR (CDCl3, 300 MHz) δ: 1.47 (s, 9H), 1.84-2.11 (m, 3H), 3.31-3.48 (m, 2H), 3.82-4.30 (m, 3H), 7.12 (dd, J=4.5, 6, 1H), 7.34-7.42 (m, 3H), 7.46-7.57 (m, 1H), 8.23 (d, J=3, 1H).
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[O:19]=[C:20]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)[CH2:21][CH2:22][C@@H:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C(#N)C.C(OCC)(=O)C.O>[CH:1]1([S:7][CH2:8][CH2:9][N:26]2[CH2:27][CH2:28][C@@H:23]([CH2:22][CH2:21][C:20](=[O:19])[C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=4)[N:37]=[CH:36][CH:35]=3)[C@@H:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:25]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)C[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C
Yield: 68.5 %

Procedure:
2.06 g of 2-chloroethyl cyclohexyl sulfide in 50 cm3 of acetonitrile, followed by 1.78 g of potassium iodide and 7.25 g of potassium carbonate, were added with stirring, at a temperature in the region of 20° C. and under an inert atmosphere, to a solution of 3.9 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate in 50 cm3 of acetonitrile. The mixture was heated for 18 hours at a temperature in the region of 80° C. After cooling to approximately 20° C., the mixture had 100 cm3 of water and 100 cm3 of ethyl acetate added. The organic phase was separated by settling, while the aqueous phase was extracted with 200 cm3 of ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 45° C. An oil was obtained, which product was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μ; diameter 3.5 cm; height 46 cm), elution was carried out with. a dichloromethane/methanol (95/5 by volume) mixture, and 50-cm3 fractions were collected. Fractions 18 to 37 were combined and concentrated as above. A product was obtained, which product was purified a second time by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μ; diameter 4 cm; height 40 cm), elution was carried out with an ethyl acetate/cyclohexane (7/3 by volume) mixture, and 100-cm3 fractions were collected. Fractions 24 to 54 were combined and then concentrated under the same conditions as above. 3.7 g of methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate were obtained in the form of an oil with a brown color.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@@H:4]([OH:7])[CH2:5][OH:6]>CO>[O:6]=[CH:5][C@@H:4]([C@H:3]([C@@H:2]([CH2:1][OH:10])[OH:9])[OH:8])[OH:7]
Reactant: OC[C@@H](O)C(O)[C@@H](O)CO
Solvent: CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
10 g (66.6 mmol) D-xylose and 10 g (65.7 mmol) xylit were mixed in 90 ml benzene and thereafter 23.3 g (138.7 mmol) ethylboroxin were added. After quantitative removal of the water/benzene-aceotrop vacuum distillation resulted in 16.4 g of III, BP 74° C./10-3Torr (yield 96%). 16.6 g residue contained the O-ethylborandiyl-derivative of the xylit. To isolate the pure D-xylose out of III 200 ml methanol were dropped to the vacuum distillate and the light volatile part currently distilled off. 9.2 g of colourless, solid D-xylose of a melting point at 142° C. were isolated (95.8% yield). The residue was mixed with 40 ml of a 1:1 mixture of ethylene-glycole/ethanol and the mixture distilled in high vacuum. The residue 10.2 g is raw xylit (yield 102%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:18])[CH:9]=2)[N:4]=1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([C:13]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:18])[CH:9]=2)[N:4]=1
Reactant: Nc1nccs1
Reactant: COc1ccc2nc(C(F)(F)F)c(C(=O)Cl)c(O)c2c1
Product: COc1ccc2nc(C(F)(F)F)c(C(=O)Nc3nccs3)c(O)c2c1

Procedure:
Using the procedure of Step F of Example 1, the product of Step F and 1.05 g of 2-amino-thiazole were reacted to obtain after crystallization from ethanol 1.6 g of 2-trifluoromethyl-6-methoxy-4-hydroxy-N-(2-thiazolyl)-3-quinolinecarboxamide melting at >270° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:3]=1.O.[NH2:24][NH2:25].Cl.O>C(O)C>[NH2:9][C:8]1[C:7]2[C:6]([Cl:10])=[N:5][C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:3][C:2]=2[NH:25][N:24]=1
Reactant: NN
Reactant: C[C@@H](NC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound (R)-1-(4,6-dichloro-5-cyanopyridin-2-yl)-3-(1-phenylethyl)urea (0.10 g, 0.29 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (0.59 mL, 0.59 mmol, 1M solution in THF) and stirred at 80° C. for 2 h. After the precipitation of white solid, the reaction mixture was cooled to room temperature and a 2M solution of HCl in water (0.29 mL, 0.59 mmol) was added stirred at same temperature for 2 h. After confirming the completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure to give crude product which was purified by preparative HPLC to afford (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.88 (s, 1H), 9.05 (s, 1H), 7.44 (s, 1H), 7.36-7.32 (m, 4H), 7.23 (d, J=8.00 Hz, 2H), 5.42 (s, 2H), 4.84-4.82 (m, 1H), 1.38 (d, J=8.00 Hz, 3H), MS ES calc'd. for C15H15ClN6O [M+H]+ 331. Found 331.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:53])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([NH2:52])=[C:25]([O:27][CH:28]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([O:37]CC5C(OC)=CC(OC)=CC=5OC)[C:31]=4[Cl:51])[CH3:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[NH2:52][C:24]1[N:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:53])=[CH:20][CH:19]=2)=[CH:26][C:25]=1[O:27][CH:28]([C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([OH:37])[C:31]=1[Cl:51])[CH3:29]
Reactant: COc1cc(OC)c(COc2ccc(Cl)c(C(C)Oc3cc(-c4ccc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)c2Cl)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(Oc1cc(-c2ccc(C(=O)N3CCNCC3)cc2)cnc1N)c1c(Cl)ccc(O)c1Cl
Yield: 62 %

Procedure:
To 140 mg 4-[4-(6-Amino-5-{1-[2,6-dichloro-3-(2,4,6-trimethoxy-benzyloxy)-phenyl]-ethoxy}pyridin-3-yl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (from general procedure 53) was added 1 mL TFA, the solution turned reddish immediately followed by addition of 100 μL triethyl silane 3 seconds later. The solution turned to yellow. After stirring for four hours 5 mL of toluene were added and the solvent was removed in vacuo. Chromatography with 10% MeOH/CH2Cl2 to 0.5% to 1% NH4OH/9.5 to 9% MeOH/90% CH2Cl2 led to 55 mg of a white solid, 62% yield.
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=2)[N:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.[Cl-:28].[Li+].N(OCCC(C)C)=O>C(#N)C.[Cu](Cl)Cl>[Cl:28][C:2]1[CH:6]=[C:5]([C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=2)[N:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [Li+]
Solvent: CC#N
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
A mixture of N-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5- yl]phenoxy}ethyl)urea 111 mg, lithium chloride 64 mg, and copper (II) chloride 81.2 mg in acetonitrile 2 ml was stirred at ambient temperature for 10 minutes. To this mixture was added isoamyl nitrite 62.3 mg, and the mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution, H2O, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH/CHCl3=10%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt/IPE to give N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea 31.1 mg as a white powder.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[F:23][C:24]([F:42])([F:41])[C:25]1[N:29]2[N:30]=[C:31]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)[CH2:32][CH2:33][C:28]2=[N:27][N:26]=1>C(Cl)Cl>[F:42][C:24]([F:23])([F:41])[C:25]1[N:29]2[N:30]=[C:31]([N:34]3[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]3)[CH2:32][CH2:33][C:28]2=[N:27][N:26]=1
Reactant: OC1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.2 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.52 g, 8.30 mmol) was added to 1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (2.0 g, 6.91 mmol) in DCM (30 mL). The resulting suspension was stirred at ambient temperature for 90 minutes. The reaction mixture was diluted with DCM (300 mL) and washed with 2M NaOH (2×200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to give 1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (0.640 g, 32%) as a solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[C:6]1[CH3:30].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]([CH3:30])=[C:7]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2cccnc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2sccc2S(=O)(=O)c2cccnc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of {5-fluoro-3-[3-(pyridine-3-sulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}acetic acid methyl ester (0.025 g) and tetrahydrofuran (0.8 mL) was treated with 2.0 M aqueous sodium hydroxide solution (0.5 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution, extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue triturated with diethyl ether to afford the title compound as a white solid (0.020 g).