Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([C:40]3[NH:1][C:2]4=[N:3][CH:4]=[C:5]([Cl:26])[C:6]([N:11]5[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]6[S:22][CH:23]=[CH:24][N:25]=6)=[O:19])[CH2:13][CH2:12]5)=[C:7]4[N:8]=3)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(Cn5cccn5)cc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.028 g, 0.07 mmol) and EtOH (3.0 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.017 g, 0.09 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.30 ml, 0.30 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.006 g, 16%); 1H-NMR (500 MHz, DMSO-d6) 2.77 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CON), 3.73 (br s, 4H, piperazine N(CH2)2), 5.41 (s, 2H, C6H4CH2N), 6.30 (t, J=1.9 Hz, 1H, pyrazole 4-H), 7.23 (d, J=3.5 Hz, 1H, thiazole H), 7.35 (d, J=7.6 Hz, 2H) and 8.14 (d, J=8.3 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.49 (d, 2H, thiazole-H, and pyrazole-H), 7.86 (d, J=1.84 Hz, 1H, pyrazole-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.89 min—534, 536 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 534.1595, calculated for C25H25ClN9OS (M+H)+: 534.1591.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH3:5].S(Cl)([Cl:26])=O>ClCCl>[ClH:26].[CH2:2]([N:6]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:1])=[O:16])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 4-(3-dibutylaminopropoxy)benzoic acid hydrochloride [19a] (3.44 g, 10.0 mmol), thionyl chloride (5.87 g, 3.6 mL, 49.4 mmol) and dichloromethane (10 mL) was stirred under reflux conditions for 1 hour and evaporated under reduced pressure at 60-70° C. (water bath) to give 3.62 g (100% yield) of 4-(3-dibutylaminopropoxy)benzoyl chloride hydrochloride [15].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30]O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>N1C=CC=CC=1>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:26]3[CH2:27][C@@H:28]([CH2:30][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)[CH2:29]3)[C:9]=2[CH3:25])[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Reactant: CN1CCNCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCN(C)CC2)C1

Procedure:
The title compound is prepared in a one pot reaction in analogy to Example 116 starting from 0.35 g (0.84 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol and 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml dry pyridine, followed by 3.5 ml (31.2 mmol) 1-methyl piperazine. Analytical HPLC: tR=8.14 min (Grad 1); ES-MS: m/eo=497.3; NMR (DMSO-d6; not all data reported): 8.08/s (1H), 7.25-7.45/several m's (6H), 7.02/“d” (1H); 6.94/s (1H); 6.89/“d” (1H); 5.4-6.0/b (NH2); 5.13/s (2H); 4.77/m (1H); 2.22/s (3H); 2.12/s (3H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[CH:9]([OH:12])[C:8](=[N:13][C:14]2[CH:19]=[CH:18]N=CC=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([N:5]1[C:10](=[O:11])[C:9]([OH:12])=[C:8]([NH:13][CH2:14][C:19]2[CH:18]=[CH:10][N:5]=[CH:1][CH:2]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1N=CC(=Nc2ccncc2)C(O)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Into 10 ml of an absolute methanol solution of 1.36 g of 2-tert-butyl-4-hydroxy-5-(4-pyridylimino)pyridazin-3-(2H)-one, 0.11 g of sodium borohydride was added in a few times under cooling with ice. Then, the mixture was stirred at room temperature for two hours. Methanol was distilled off under reduced pressure, and then 100 ml of water and 150 ml of ethyl acetate were added thereto, followed by shaking. The insoluble powder was collected by filtration and washed with deionized water and then with diethyl ether (containing a small amount of ethyl acetate), and then dried under suction to obtain 0.71 g of the desired product (Compound No. 45) having a melting point of from 243° to 245° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1CCCCC1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:18]([OH:20])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[N:10]2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(F)c1)C(=O)OCC
Solvent: C1CCCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(F)c(OC)cc2c1O
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A stirred solution of 37.75 g of diethyl 2-[(3-fluoro-4-methoxyphenylamino)methylene]malonate in 170 cm3 of diphenyl ether is brought to 245° C. for 3.5 hours. After cooling to ambient temperature, 220 cm3 of cyclohexane are added, and the precipitate thus obtained is filtered off and washed with cyclohexane and then with pentane and is spin-filtered to dryness. 24.10 g of ethyl 7-fluoro-4-hydroxy-6-methoxy-quinoline-3-carboxylate are obtained, in the form of a solid which melts at 280° C.
Reaction SMILES: Cl.[N:2]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([OH:17])[C:13]=3[CH:18]=2)[CH3:8])[CH:6]=[CH:5][N:4]=[CH:3]1.I[CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:20]([O:17][N:14]1[C:13]2[CH:18]=[C:9]([CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[CH:3]3)[CH3:8])[CH:10]=[CH:11][C:12]=2[N:16]=[N:15]1)[CH3:21]
Reactant: CCI
Reactant: CC(c1ccc2nnn(O)c2c1)n1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOn1nnc2ccc(C(C)n3ccnc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture of 4.5 parts of 6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazol-1-ol monohydrochloride, 3.12 parts of iodoethane, 3.7 parts of sodium carbonate and 63 parts of N,N-dimethylformamide was stirred for 4 hours at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 27 parts of ethyl acetate and 21 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.26 parts (51.6%) of 1-ethoxy-6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazole; mp. 81.1° C. (compound 215).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[CH2:14][C:15]1[C@H:16]([CH3:38])[C@@H:17]2[C@@H:27]([C@H:28]([O:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH3:29])[C:26](=[O:37])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21].[S:39]1(=[O:55])(=[O:54])[C:43]2[CH:44]=[CH:45][C:46]3[CH2:47][NH:48][CH2:49][C:50]4[C:53]=3[C:42]=2[C:41](=[CH:52][CH:51]=4)[NH:40]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:38][C@@H:16]1[C@@H:17]2[C@@H:27]([C@H:28]([O:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH3:29])[C:26](=[O:37])[N:18]2[C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[C:15]1[CH2:14][N:40]1[C:41]2[C:42]3[C:53]4[C:50](=[CH:51][CH:52]=2)[CH2:49][NH:48][CH2:47][C:46]=4[CH:45]=[CH:44][C:43]=3[S:39]1(=[O:55])=[O:54]
Reactant: O=S1(=O)Nc2ccc3c4c(ccc1c24)CNC3
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccc5c6c(ccc(c46)S3(=O)=O)CNC5)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethylazodicarboxylate (2.25 mmol) is added to a cold (0° C.) solution of allyl (1S,5R,6S)-2-(hydroxymethyl)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methylcarbapen-2-em-3-carboxylate (1.5 mmol), 2,5,6,7-tetrahydro-1-thia-2,6-diaza-cyclopenta[cd]phenalene-1,1-dioxide (1.5 mmol) and triphenylphosphine (2.25 mmol) in tetrahydrofuran (15 mL). The mixture is stirred at room temperature for 30 minutes then partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer is extracted with ethyl acetate (50 mL) and the combined ethyl acetate layers are washed with saturated aqueous sodium chloride (50 mL), dried with magnesium sulfate, filtered, and evaporated. The crude product is purified by column chromatography to give the title compound.
Reaction SMILES: CS[C:3]1[CH:13]=[CH:12][C:11](CCCC2C=CC=CC=2)=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:31])=O>C(Cl)Cl>[C:7]([Cl:31])(=[O:8])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1ccc(CCCc2ccccc2)cc1C=CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To dry methylene chloride (32 ml) there is added 2-methylthio-5-(3-phenylpropyl)cinnamic acid (1.0 g, 3.2 mmol). To this mixture is added DMF (0.25 ml, 3.2 mmol) and the reaction mixture cooled in an ice bath. Oxalyl chloride (.61 ml, 7.04 mmol) is slowly added dropwise and the resulting mixture stirred at room temperature for 2 hours to afford 2-methylthio-5-3-phenylpropyl)cinnamic acid chloride in solution.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 436 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a stirred suspension of NaH (60%, 0.146 g, 3.65 mmol) in DMF (15 mL) was added dropwise a solution of 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.611 g, 3.04 mmol) in DMF (5 mL) at 0° C. The reaction was stirred for 1 hour and then 4-chloroquinazoline (0.500 g, 3.04 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 2:1) to give 4-(Quinazolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.76 g, 76%) as a colorless oil. Removal of the Boc group by the procedures described in Example 34, Step 3 afforded 4-(Piperidin-4-yloxy)-quinazoline dihydrochloride as a white solid. 1H NMR (CD3OD, 400 MHz) δ 9.35 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.31 (td, J=7.2 Hz, J=1.2 Hz 1H), 8.11 (d, J=8.4 Hz, 1H), 8.04 (t, J=7.2 Hz, 1H), 6.00 (m, 1H), 3.55 (m, 2H), 3.40 (m, 2H), 2.42 (m, 4H). LCMS (APCI+) m/z 230 [M+H]+; Rt=1.67 min.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([Br:14])=[CH:9][C:8]=1[CH3:15].[C:16](=[O:18])=[O:17].Cl>CCCCCC>[Br:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH3:15])[CH:9]=1
Reactant: Cc1cc(Br)c(C)cc1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −78° C., 100 ml (0.16 mol) of a 1.6 molar n-butyl lithium solution in hexane is added dropwise to a solution of 43.63 g (0.162 mol) of 2,5-dibromo-p-xylene, and stirred for one hour. Then dry carbon dioxide is passed into the solution for 4 hours. It is slowly heated to ambient temperature and stirred for 16 hours. After the slow addition of 210 ml of 2N hydrochloric acid, the phases are separated, the aqueous phase is extracted 2× with 200 ml ether, the combined organic phases are washed with conc. NaCl solution and dried with Na2SO4. After the solvent has been eliminated in vacuo the crude product is mixed with 200 ml of 2N NaOH and the brown solution obtained is extracted 3× with 100 ml of diethyl ether. The aqueous phase is acidified with conc. HCl and the precipitate which then forms is suction filtered, washed with ice water and dried.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1.[Na+].[I-].Cl.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:28][CH2:27]1
Reactant: BrCCCOc1ccc2cn[nH]c2c1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Clc1cccc(N2CCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
A mixture of intermediate 44 (84 mg, 0.31 mmol) and NaI (94 mg, 0.63 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 41 (125 mg, 0.47 mmol) and anhydrous K2CO3 (172 mg, 1.25 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=40:1) to give 6-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)-1H-indazole (compound 20) (90 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.97 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.16-7.14 (m, 2H), 6.98-6.95 (m, 1H), 6.87-6.82 (m, 2H), 4.10 (t, J=6.6 Hz, 2H), 3.10 (m, 4H), 2.71-2.63 (m, 6H), 2.10-2.04 (m, 2H). HPLC: 99%, RT 2.462 min. MS (ESI) m/z 405.2 [M+H]+. mp: 159-161° C.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[C:26]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH:37](=O)[CH3:38].[BH3-]C#N.[Na+]>CO.CC([O-])=O.[Na+]>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[C:26]([O:28][CH:29]4[CH2:30][CH2:31][N:32]([CH2:37][CH3:38])[CH2:33][CH2:34]4)[CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC=O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCN1CCC(Oc2ccnc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a stirred solution of N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride from Example 1 (100 mg, 0.19 mmol) in 2 mL of pH˜4 MeOH/NaOAc buffer (21 grams of NaOAc.3H2O and 48 mL of AcOH, diluted to 1.0 L with methanol) was added acetaldehyde (0.2 mL, excess) and NaCNBH3 (25 mg, excess). The resulting mixture was stirred at rt for 3 h. LC-MS indicated that the reaction was complete. The crude product was purified by reverse phase HPLC to afford N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(1-ethylpiperidin-4-yloxy)picolinamide as a white powder (52 mg, 53% yield). LC-MS (ESI) m/z 507 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.49 (s, 1H), 8.79 (s, 1H), 8.54 (d, J=5.65 Hz, 1H), 7.83 (d, J=9.04 Hz, 2H), 7.67 (br. s., 1H), 7.43 (d, J=8.85 Hz, 2H), 7.26 (dd, J=2.45, 5.65 Hz, 1H), 6.50 (s, 1H), 4.82 (br. s., 1H), 2.75-3.14 (m, 3H), 2.07 (br. s., 2H), 1.75 (br. s., 2H), 1.30 (s, 9H), 1.13 (br. s., 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][OH:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][O:28][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(CO)CC3)c2-c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-methanol (Example 1, Compound E, 2.0 g) in dichloromethane (30 mL) is added sequentially pyridine (0.60 mL), methanesulfonyl chloride (0.55 mL), and 4-dimethylaminopyridine (0.06 g) at 0° C. under a nitrogen atmosphere. The mixture is stirred at 0° C. for 30 minutes and is warmed to room temperature. The mixture is stirred at room temperature for four hours and is then diluted with dichloromethane (30 mL.) The mixture is washed 0.5 N hydrochloric acid solution and with brine solution. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography to afford the synthetic intermediate methanesulfonic acid 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropylmethyl ester (2.35 g.)
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH3:16])=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:18]1([NH:21][C:22]([NH2:24])=[NH:23])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:18]1([NH:21][C:22]2[N:24]=[C:5]([C:7]3[C:8]([CH3:16])=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:23]=2)[CH2:20][CH2:19]1
Reactant: Cc1nn2ncccc2c1C(=O)/C=C/N(C)C
Reactant: N=C(N)NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn2ncccc2c1-c1ccnc(NC2CC2)n1
Temperature: 135 °C
Yield: 38 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (50 mg, 0.22 mmol) in DMF (2.5 mL) was added N-cyclopropylguanidine.0.5H2SO4 (130 mg, 0.66 mmol) and potassium carbonate (152 mg, 1.10 mmol). The reaction was heated at an oil bath temperature of 135° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then disolved in CH2Cl2 and triturated with diethylether to give the title compound as a yellow solid (22 mg, 38%). 1H-NMR (300 MHz, CDCl3) δ 9.02 (d, 1H, J=8.8 Hz), 8.39 (d, 1H, J=5.2 Hz), 8.35 (dd, 1H, J=4.4, 2.0 Hz), 7.15 (dd, 1H, J=8.8, 4.4 Hz), 6.94 (d, 1H, J=5.3 Hz), 5.45 (s, 1H), 2.89 (m, 1H), 2.83 (s, 3H), 0.91 (m, 2H), 0.68 (m, 2H); MS (ESI) (M+H)+ 267.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 43.5 %

Procedure:
The title compound was prepared by following the procedure as described for step-6 of Intermediate-26 by using methyl 4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate (Intermediate-46, 0.070 g, 0.17 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.048 g, 0.26 mmol), trimethyl aluminum (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.040 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.49-7.64 (m, 4H), 7.72-7.76 (m, 3H), 7.99 (m, 1H), 8.25 (m, 1H), 10.52 (s, 1H), 12.86 (s, 1H); MS (m/z): 541.05 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[C:5][CH2:6][Cl:7].O.[OH-].[Na+].[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[C:11]([O:15][C:16]([NH:2][CH2:3][C:4]#[C:5][CH2:6][Cl:7])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCC#CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCC#CCCl
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Ex-8c) 14.1 g of 1-Amino-4-chloro-2-butyne hydrochloride was taken up in 70 mL of dioxane and :35 mL water. 4 g NaOH was added and the reaction mixture was stirred for 30 minutes followed by the addition of 21.8 g di-t-butylcarbonate at 20° C. The reaction mixture was stirred at 20° C. to 25° C. for 8 h and then the lower organic layer was separated. The upper aqueous layer was extracted with 100 mL of dichloromethane. Organic layers were combined and washed with 50% aqueous NaHCO3, dried over anhydrous MgSO4, treated with Darco, filtered over celite and concentrated to give a brown oil. This oil was chromatographed to give 9 g of 1-t-Butyloxycarbonylamino-4-chloro-2-butyne as a white solid.