Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])[CH:16]=2)=[N:3]1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (533 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (701 mg, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=1[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(F)ccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 35.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,5-difluorophenylboronic acid (Aldrich; 529 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,5-difluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (305 mg, 35%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].CCN(C(C)C)C(C)C>C1COCC1>[CH3:19][O:20][CH2:21][C:22]([NH:11][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:2]=2[CH3:1])[CH:10]=[CH:9][N:8]=1)=[O:23]
Reactant: COCC(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine [WO2007059257] (405 mg, 1.65 mmol) in THF (5.0 mL) at 0° C. was added 2-methoxyacetyl chloride (604 μL, 6.61 mmol) and DIPEA (1.44 mL, 8.26 mmol) and the reaction mixture warmed to RT for 30 min. The reaction was quenched by addition of a 1% solution of NH3 in MeOH (3.0 mL) and was kept at RT for 16 hr. A second aliquot of a solution of NH3 in MeOH (7M, 1.0 mL) was added and after 30 min at RT the resulting mixture was evaporated in vacuo. The residue was subjected to SCX capture and release to afford 2-methoxy-N-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide as an orange oil (357 mg, 92% pure, 63%); Rt 2.07 min (Method 2); m/z 318 (M+H)+ (ES+), which was used directly in the next step (below).
Reaction SMILES: C(Cl)Cl.[C:4](OC(=O)C)(=[O:6])[CH3:5].[OH:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:4]([O:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:6])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(-c2cccnc2)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2cccnc2)cc1C(=O)O
Temperature: 25 °C

Procedure:
Methylene chloride (5.0 mL), pyridine (0.25 mL), and acetic anhydride (0.19 mL) were sequentially added to the obtained 2-hydroxy-5-(pyridin-3-yl)benzoic acid, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then pyridine (0.082 mL) and acetic anhydride (0.095 mL) were added thereto, followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-93% chloroform/methanol] to obtain 0.035 g of 2-acetoxy-5-(pyridin-3-yl)benzoic acid as a white solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.Cl[C:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([C:10]([F:13])([F:12])[F:11])[CH3:9].[OH-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:8]([C:10]([F:11])([F:13])[F:12])([CH3:9])[C:5]#[N:6])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(C)(Cl)C(F)(F)F)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C(C)(C#N)C(F)(F)F)cc1
Yield: 93 %

Procedure:
Trimethylsilyl cyanide (65.1 ml; 423 mmol) was added at room temperature to 1-chloro-1-(4-methoxyphenyl)-1-trifluoromethylethane (77.6 g; 335.5 mmol) in methylene chloride (975 ml) followed by titanium tetrachloride (32.5 ml; 3.25 mmol). After stirring for 20 hours at room temparature, 2N sodium hydroxide was added carefully, dropwise, until the mixture was neutral and the precipitate separated over celite. The aqueous phase was extracted with ethyl acetate and the extract dried over sodium suphate. After concentrating, there was obtained 2-(4-methoxyphenyl)-2-trifluoromethylpropionitrile (71.49 g=90% of theory).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([F:8])=[C:6]([CH2:9]O)[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4]1)[CH3:2].P(Br)(Br)[Br:16]>C(OCC)C>[Br:16][CH2:9][C:6]1[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[F:8]
Reactant: BrP(Br)Br
Reactant: CCn1nc(C(F)(F)F)c(CO)c1F
Solvent: CCOCC
Product: CCn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A solution of 9.1 g (42.9 mmoles) of (1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 12.2 g (45.0 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain a crude product of 4-bromomethyl-1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: C=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (300 mg, 0.67 mmol) and paraformaldehyde (201 mg, 6.7 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropylamine), 175 mg (57%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:50])[C:5]2[N:6]=[CH:7][N:8]([C:48]=2[N:49]=1)[C@@H:9]1[O:47][C@H:34]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[C@@H:22]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C@H:10]1[O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][OH:60])=[CH:54][CH:53]=1>>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][C:2]2[N:3]=[C:4]([NH2:50])[C:5]3[N:6]=[CH:7][N:8]([C:48]=3[N:49]=2)[C@@H:9]2[O:47][C@H:34]([CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:44]([CH3:46])[CH3:45])[C@@H:22]([O:23][Si:24]([CH:31]([CH3:32])[CH3:33])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:26])[CH3:27])[C@H:10]2[O:11][Si:12]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[CH:54][CH:53]=1
Reactant: CC(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]1O[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Reactant: OCCc1ccc(Cl)cc1
Product: CC(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]1O[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 2-chloro-2′,3′,5′-tris-O-(triisopropylsilyl)adenosine (Example 6, 5.0 g) and 15 ml of 2-(4-chlorophenyl)ethyl alcohol was purged with nitrogen and heated to 50° C. Sodium hydride (1.56 g, 60% dispersion in mineral oil) was added at a rate so as to control gas evolution. After 48 hours of heating LC and LC/MS analysis showed a mixture of products with one and two protecting groups respectively (2 isomers). The reaction mixture was allowed to cool to room temperature and carefully quenched with 40 mL of water. The resulting mixture was extracted with ethyl acetate (70 ml). The layers were separated and the aqueous layer was again extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (80 mL), dried over MgSO4 and concentrated under reduced pressure to afford a clear oil (18 g). This was purified by silica gel chromatography eluting progressively with CH2Cl2, 1%, 2%, 5% and then 10% MeOH in CH2Cl2. The fractions containing the desired products were combined and concentrated to yield 3.2 g of a gummy white solid. This mixture of silylated displacement products was taken to the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH:29]([C:31]1[O:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:34]4[O:35][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.2 g, 0.45 mmol) and (5-formylfuran-2yl)boronic acid (0.075 g, 0.542 mmol), in dioxane/water mixture (4 mL+1 mL), Cs2CO3 (0.368 g, 1.13 mmol) was added and solution purged with argon for 15 min. Pd(PPh3)4 (0.052 g, 0.045 mmol) was then added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 2 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-6-(5-formylfuran-2yl)-1H-indazole-4-carboxamide (0.09 g, 43.4%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11](=[O:19])OC1C=CC=CC=1.Cl.[CH3:21][S:22]([N:25]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26]1)(=[O:24])=[O:23]>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[NH:10][C:11]([N:30]1[CH2:31][CH2:32][C:27]2([C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH2:26]2)[CH2:28][CH2:29]1)=[O:19]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C(NC1Cc2ccccc2C1)Oc1ccccc1
Agent: Cl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3Cc4ccccc4C3)CC2)c2ccccc21

Procedure:
Compounds of Examples 85 to 88 were obtained by following the same procedure as in Example 84, except that phenyl N-(2-indanyl)carbamate and 1-methanesulfonylspiro[indoline-3,4′-piperidine]hydrochloride used in Example 84 were replaced with the corresponding starting materials of each desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1.O>CN(C)C(=O)C>[CH3:22][C:18]1[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 9 °C
Yield: 63.9 %

Procedure:
4-aminophenol (44.9 g, 410 mmol) was added to the 1 L 3-neck flask and dissolved with N,N-dimethylacetamide (600 mL). The stirred mixture was then cooled to 9° C. and potassium t-butoxide (46.18 g, 410 mmol) was added portionwise; the solution turned green and solidified before potassium t-butoxide addition was completed. Stirring was reestablished and a solution containing the 4-chloro-2-picoline (50 g, 390 mmol) in N,N-dimethylacetamide (400 mL) was slowly added and the mixture was heated at 90° C. for 17 h. The mixture was then allowed to cool to 45° C., filtered and concentrated to near dryness in vacuo to leave brown residue. The residue was slowly added to vigorously stirred water (1 L) and the suspension was stirred for 1 hr. The solids were then collected by suction filtration and washed with small amount of isopropanol, ether and dried to afford {4-[(2-Methylpyridin-4-yl) oxy] phenyl} amine (49.9 g, 64%) as light tan solid. 1H NMR (DMSO-d6) δ 8.21 (d, 1H), 6.78 (d, 2H), 6.57-6.63 (m, 4H), 5.10 (s, 2H), 2.35 (s, 3H); MS ES 201 (M+H)+, calcd 201, RT=1.04 min.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:26]([CH:23]5[CH2:25][CH2:24]5)=[O:27])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)cc1
Product: O=C(Nc1ccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)cc1)C1CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 170, starting from 4-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine and cyclopropanecarbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.93 (d, 2H), 7.86 (d, 1H), 7.67 (d, 2H), 7.30 (d, 1H), 3.57-3.54 (m, 4H), 2.64-2.62 (m, 4H), 1.79-1.74 (m, 1H), 1.65-1.62 (m, 1H), 0.78 (d, 4H), 0.43-0.41 (m, 2H), 0.35-0.30 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:34][CH:35]([NH2:38])[CH2:36][OH:37]>C(Cl)(Cl)Cl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH:35]([CH3:34])[CH2:36][OH:37])[N:7]=3)=[C:16]3[N:11]([N:12]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:14][CH2:15]3)[N:10]=2)=[CH:28][CH:29]=1
Reactant: CC(N)CO
Reactant: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Solvent: ClC(Cl)Cl
Product: CC(CO)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCCN3C(=O)OCc2ccccc2)n1

Procedure:
A solution of phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-5,6-dihydropyrazolo[1,5-b]pyridazine-7(4H)-carboxylate (i.e. the product of Example 4, Step C) (390 mg, 0.84 mmol) and DL-2-amino-1-propanol (2.62 mL, 3.36 mmol) in chloroform (3 mL) was heated at 120° C. in a sealed tube under microwave irradiation for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by medium pressure liquid chromatography using 10-80% ethyl acetate in hexanes as eluant to give 150 mg of the title compound as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:10](OC)=[O:11]>CO>[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]=[O:11])[CH2:6][CH2:5]1
Reactant: NCCN1CCNCC1
Reactant: COC=O
Solvent: CO
Product: NCCN1CCN(C=O)CC1
Yield: 48.2 %

Procedure:
Corresponding to Example 1, 774.3 g (6.00 mol) of N-2-aminoethylpiperazine in 300 ml of methanol were reacted with 120.0 g (2.00 mol) of methyl formate and 151.6 g (48% of theory) of N-2-aminoethyl-N'-formylpiperazine were obtained at 0.1 mm Hg between 115 and 120° C. in the form of a yellowish liquid
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:7])=[O:6].[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][CH2:21][CH:20]=[CH2:19])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:6])=[O:7]
Reactant: CN(C)C=NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccc2nc(S(=O)(=O)N=CN(C)C)sc2c1
Temperature: 60 °C
Yield: 70.7 %

Procedure:
A solution of product from Step A (1.14 gm, 4.0 mmol) and allyl bromide (0.5 mL, 5.5 mmol) in dimethyl sulfoxide (8 mL) containing potassium carbonate (0.75 gm, 5.4 mmol) was warmed at 60° C. for 15-20 hours. The reaction mixture was poured into water and the product was extracted into ethyl acetate, dried (Na2SO4) and evaporated to give a viscous oil (0.92 gm).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:18][CH2:19][OH:20])([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.C(N(C(C)C)CC)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:15][CH2:16][O:17][S:31]([CH3:30])(=[O:33])=[O:32])([CH2:18][CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[C:12](=[O:14])[N:13]=1
Reactant: O=C1N=C(NC2CC3CCC2C3)SC1(CCO)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)SC(NC2CC3CCC2C3)=NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5,5-bis(2-hydroxyethyl)thiazol-4(5H)-one (280 mg, 0.94 mmol) and diisopropylethylamine (Aldrich, 412 mg, 3.19 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (344 mg, 3.00 mmol, 3.2 eq), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated in vacuo to providethe title compound which was used without further purification. MS (ESI, pos. ion) m/z: 455 (M+H).
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[CH2:20][CH2:21][CH3:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:23]1([C:2]2[NH:6][CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=2[CH2:20][CH2:21][CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1Br
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: [Na+]
Product: CCCc1c(C(=O)OC)c[nH]c1-c1ccccc1
Yield: 80.2 %

Procedure:
Using methyl 5-bromo-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carboxylate (3.96 g), phenylboronic acid (2.5 g), tetrakis(triphenylphosphine)palladium (1.79 g) and sodium carbonate (3.28 g), a procedure as in Reference Example 56 was performed to give the title compound as a pale-yellow oil (yield 2.0 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.OS(O)(=O)=O.[CH3:16]O>C(Cl)Cl>[CH3:16][O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cn1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A mixture of 5-bromo-2-pyridine carboxylic acid (26.2 g, 0.124 mol) and conc. H2SO4 (12.5 mL) in MeOH (250 mL) was heated to 60° C. and diluted with additional MeOH (250 mL). After 18 h at 60° C., the mixture was cooled to rt, diluted with DCM, and washed with a solution consisting of 21 g KOH in 200 mL water, sat. K2CO3, and water. The organic layer was dried and concentrated to give the title compound (21.4 g, 76%) as a white solid. This material was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.CC([O-])(C)C.[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=3)[CH:3]=[N:2]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3ccc(C=O)cc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a solution of 1H-indazole-6-carbaldehyde (1.5 g, 10.3 mmol) in DMF (10 mL) at 0° C. was added KOtBu (1.4 g, 12.4 mmol) and let stir for 10 min. PMBCl (1.7 mL, 12.4 mmol) was then added and let slowly warm to room temperature. After 1.5 h the reaction was quenched with NH4Cl. The product was extracted with Et2O and the organic layers was washed brine and then dried over MgSO4. The solvent was removed and the crude material (mixture of N1 and N2 isomers) was dried under high vacuum. To the resulting residue was added PMBCl (0.70 mL, 5.15 mmol) and the mixture heated to 170° C. for 2.5 h. Cooled to room temperature and purified residue using Biotage Isolera (silica gel, 20-50% EtOAc in hexane) which gave the title compound (1.97 g, 72%). 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.62 (s, 2H), 3.77 (s, 3H); MS ESI 266.9 [M+H]+, calcd for [C16H14N2O2+H]+ 267.1.