Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=3)[N:11]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:10]=2)O1.Cl[C:41]1[C:46]([C:47]#[N:48])=[CH:45][N:44]=[C:43]([S:49][CH3:50])[N:42]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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.Cl[Pd]Cl.[Fe+2]>[C:47]([C:46]1[C:41]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:16]=3)[N:11]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[CH:10]=2)=[N:42][C:43]([S:49][CH3:50])=[N:44][CH:45]=1)#[N:48]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ncc(C#N)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(NC(=O)OCc4ccccc4)cc23)n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
Benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (0.50 g, 0.91 mmol) in toluene/ethanol (7.5 mL:2.0 mL) was treated with 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (0.186 g, 1.00 mmol, 1.1 Eq) and 2M aqueous potassium carbonate (1.37 mL, 2.74 mmol, 3.0 Eq), degassed and stirred under nitrogen for 20 minutes. Pd(dppf)2Cl2 (0.075 g, 0.1 Eq) was added and the mixture allowed to heat at 100° C. for 1.5 hours. The reaction was partitioned between EtOAc and saturated aqueous sodium carbonate and the organic layer separated, dried over magnesium sulphate and evaporated to dryness. The mixture was purified by column chromatography eluting with 10% EtOAc/Petroleum ether to yield a white solid (0.219 g, 42%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCC1CC1
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(cc1OCC1CC1)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1 intermediate d), from (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate), sodium hydride and (bromomethyl)cyclopropane.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[O:24]1[CH2:29][CH2:28][O:27][C:26]2=[C:30]([C:33](O)=[O:34])[S:31][CH:32]=[C:25]12>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:30]2[S:31][CH:32]=[C:25]3[C:26]=2[O:27][CH2:28][CH2:29][O:24]3)=[O:34])=[O:8])[N:6]=1
Reactant: O=C(O)c1scc2c1OCCO2
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2scc3c2OCCO3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,3-Dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=501.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O>[NH:31]1[C:28]2=[N:29][CH:30]=[C:25]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)[CH:26]=[C:27]2[CH:33]=[CH:32]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CNc2ncc(-c3cnc4[nH]ccc4c3)nc2N1CCC1CCOCC1
Temperature: 100 °C
Yield: 11.2 %

Procedure:
1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.0 g, 2.352 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.556 g, 2.82 mmol), tris(dibenzylideneacetone)palladium(0) (0.237 g, 0.259 mmol), tri-o-tolylphosphine (0.158 g, 0.518 mmol) and triethylamine (0.984 mL, 7.06 mmol) were combined in a sealed tube, dimethylformamide (5 mL) was added. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas. The reaction was heated to 100° C. for 1 h. After cooling to room temperature, the reaction mixture was filtered through Celite. The filter cake was washed with ethyl acetate. The wash and filtrate were combined and concentrated nearly to dryness. The resulting solid was dissolved in hot methanol, filtered through Celite and purified by reverse-phase preparative HPLC (5-80% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). The clean fractions were collected, neutralized with ammonium hydroxide and concentrated to dryness. The solid obtained was filtered, washed with water and dried under high vacuum to yield the title compound (0.10 g, 0.264 mmol, 11.2% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.71 (br. s., 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.49 (d, J=10.54 Hz, 2H), 6.48 (br. s., 1H), 4.18 (s, 2H), 4.13 (t, J=6.44 Hz, 2H), 3.82 (d, J=12.89 Hz, 2H), 3.27 (t, J=11.13 Hz, 2H), 1.71 (d, J=12.49 Hz, 2H), 1.60 (br. s., 3H), 1.24 (d, 2H); MS (ESI) m/z 379.2 [M+1]+; mp 255-258° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[N:14]([C:15](=[O:38])[C@@H:16]([NH:20]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH:17]([CH3:19])[CH3:18])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2].N1CCCCC1>C(#N)C>[NH2:20][C@@H:16]([CH:17]([CH3:18])[CH3:19])[C:15]([N:14]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH:6]1[C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[O:38]
Reactant: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (2S)-1-(2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (85 mg, 166 μmol, Eq: 1.00) in acetonitrile (4 mL) was added piperidine (0.1 mL, 1.01 mmol, Eq: 6.09) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM/EtOAc (˜1:10) and the combined organic layers were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give 1-((S)-2-amino-3-methylbutanoyl)-N-ethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (39 mg), m/z=291 (M+H).
Reaction SMILES: C([O:8][C:9](=[O:36])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C@@H:28]([C:31]([O:33]CC)=[O:32])[O:29][CH3:30])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[OH-].[Na+]>>[C:31]([C@@H:28]([O:29][CH3:30])[CH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([OH:36])=[O:8])=[CH:11][CH:12]=2)=[CH:26][CH:25]=1)([OH:33])=[O:32]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(C(=O)OCc3ccccc3)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)O)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-4-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid benzyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS (ES) for C20H22O7 [M+Na]+: 397.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([OH:19])[CH2:16][CH:15]2[C:20](=[O:29])[N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])[CH3:22])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:40][O:41][CH2:42][CH3:43]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][CH2:40][O:41][CH2:42][CH3:43])[CH2:16][CH:15]2[C:20](=[O:29])[N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])[CH3:22])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reactant: CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(OCOCC)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the diene 1c (7.94 g, 0.02 mol) in DCM and DIPEA (9.7 ml, 6 eq) at 0° C. (ice-bath) was added chloromethylethyl ether (2.79 g, 3 eq). The reaction mixture was stirred at room temperature overnight, concentrated by rotary evaporation and purified by column chromatography on silica gel (EtOAc/petroleum ether 1:1→1:0) which gave the pure title compound as slightly yellow syrup (6.67 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.Br[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:30]([O:18][C:11]1[CH:10]=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]([F:15])([F:17])[F:16])[N:12]=1)[CH3:31]
Reactant: CS(=O)(=O)c1ccc(-c2cc(=O)[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c(C(F)(F)F)n1
Reaction time: 20 h
Yield: 26.4 %

Procedure:
A mixture of 0.11 g of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-oxo-pyridine (step 5 of Example 1), 3,3 g of bromoethane, 0.2 g of potassium carbonate, and 5 mL of dimethyl formamide (DMF) was stirred for 20 hours and concentrated in vacuo. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO4 and filtered through silica gel. The filtrate was reconcentrated in vacuo and the residue was crystallized from methylene chloride/hexane to give 31 mg of solid: mp 168.5°-170.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(OC)ccc4nc3OC)CC2)c1
Yield: 80 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 80%). 1H NMR (300 MHz, CDCl3): δ 3.28 (s, 4H), 3.80-3.87 (m, 9H), 4.11 (s, 4H), 6.45-6.49 (m, 2H), 6.56 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 7.04-7.36 (m, 3H), 7.53-7.62 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1.[OH-].[Na+].Cl>CS(C)=O.C(OCC)(=O)C.O>[S:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: OC1CNC1
Reactant: ClCCCOCCc1ccc2sccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: OC1CN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 64.2 %

Procedure:
In 30 mL of dimethyl sulfoxide was dissolved 6.50 g of 5-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and to the solution were added 5.60 g of 3-azetidinol hydrochloride and 15.3 mL of a 5 mol/L aqueous sodium hydroxide solution, after which the resulting mixture was stirred at 65° C. for 3.5 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10 with a 5 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=30:1 to 10:1) to obtain 4.77 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCC(C1C=CC=C2C=1N=C(NC1(C)CC1)C(C)=N2)=O.C(OC(NC1(C(=O)CC(OCC)=O)CC1)=O)(C)(C)C>CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]3([CH3:36])[CH2:35][CH2:37]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: Cc1nc2cccc(C(=O)CBr)c2nc1NC1(C)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4(C)CC4)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 76 %

Procedure:
This compound (930 mg, 1.84 mmol, 76% yield) as a yellow amorphous solid was prepared according to the procedures described for Intermediate 324b, using 2-bromo-1-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (611) (810 mg, 2.42 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (789 mg, 2.91 mmol) as the starting materials, followed by the subsequent treatment of the resulting 329a (m/z (ESI, +ve) 525.2 (M+H)+) with NH4OAc (1.12 g, 14.54 mmol) in 3 mL of EtOH and 1.5 mL of HOAc at 50° C. for 4 h. m/z (ESI, +ve) 506.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.Cl[C:11]1C=C(C)C(=O)N(C)N=1>>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[N:7]=1
Reactant: Cc1cc(=O)[nH]nc1Cl
Reactant: Cc1cc(Cl)nn(C)c1=O
Product: Cc1cc(=O)n(C)nc1Cl

Procedure:
The title intermediate was prepared from 6-chloro-5-methyl-2H-pyridazin-3-one following a procedure analogous to that described for intermediate 6-chloro-2,4-dimethyl-2H-pyridazin-3-one in Example 17*. Mass spectrum (ESI+): m/z=159/161 (CI) [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11](C(O)=O)[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:39][C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(F)ccc1[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of (3R,4R)-1-(tert-butoxycarbonyl)-3-(4-fluoro-2-methylphenyl)piperidine-4-carboxylic acid (4.33 g) synthesized by a known method (WO2006/004195) in toluene (24 mL) were added DPPA (5.30 g) and triethylamine (2.7 mL) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction solution was cooled, 8N aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→70% ethyl acetate/hexane) to give the title compound (3.79 g, 96%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:11]=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:5][CH2:4][N:3]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[NH4+].[Cl-]>CO.O.[Zn]>[NH2:18][C:9]1[CH:10]=[N:11][N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:8]=1[N:6]1[CH2:5][CH2:4][N:3]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CN(c2c([N+](=O)[O-])cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC1CN(c2c(N)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of (±) tert-butyl 2-methyl-4-(4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)piperazine-1-carboxylate (370 mg, 0.94 mmol) in MeOH (15 mL) and H2O (3 mL) was added zinc (362 mg, 5.6 mmol) and NH4Cl (400 mg, 7.5 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, filtered through Celite, and evaporated under reduced pressure to afford tert-butyl (±)-4-(4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate as yellow solid (300 mg, 88%). MS (ESI) m/z: 364 [M+H+].
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1C=O>CC(O)=O.CC(N(C)C)=O>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:2]1[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[CH:8][N:7]=[C:6]([C:11]1[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=13)[N:5]=2
Reactant: Cn1ccnc1C=O
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cn1ccnc1-c1nc2cnc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 140 °C
Reaction time: 19 h
Yield: 31 %

Procedure:
To a solution of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in AcOH (0.025 mL) and DMA (2.5 mL), 1-methyl-1H-imidazole-2-carbaldehyde (46 mg, 0.42 mmol) was added. The reaction mixture was stirred in a sealed tube at 140° C. for 19 h. The crude mixture was quenched with H2O (10 mL), extracted with EtOAc (3×10 mL) and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 40 mg of the desired compound (31% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.S(O[CH2:36][CH2:37][O:38][CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>CN(C=O)C>[F:17][C:13]1[CH:12]=[C:11]([NH:10][N:9]=[C:4]2[C:3]([CH2:2][N:1]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:7][N:6]=[C:5]2[NH2:8])[CH:16]=[CH:15][CH:14]=1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC1=NN=C(CN2CCOCC2)C1=NNc1cccc(F)c1
Temperature: 87 °C
Yield: 17.1 %

Procedure:
To a mixture of 5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg, 0.25 mmole) and triethylamine (71 μL, 0.512 mmole) in 3 mL of anhydrous DMF was added solid di(2-tosyloxyethyl)ether (108 mg, 0.25 mmole). The reaction was heated at 87° C. for 5-6 hours, and was then worked up by the addition of saline and ethyl acetate. The crude material was purified by preparative TLC (CH2Cl2:CH3OH=15:1) to yield 13 mg of the title compound as a yellow powder. MS (m/z, ES+): 305 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 7.53 (m, 1H), 7.40 (m, 2H), 7.03 (m, 1H), 6.45 (br s, 2H), 3.97 (s, 2H), 3.74 (m, 4H), 2.65 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[OH:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:16]
Reactant: Cc1cc(Br)cc2c(O)c(C(=O)O)cnc12
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(Br)cc2c(O)ccnc12
Temperature: 260 °C
Yield: 94.4 %

Procedure:
A mixture of 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid (1.80 g, 6.36 mmol) and Dowtherm A (10 mL) was heated at 260° C. for 1.0 h. The reaction was cooled, triturated with hexanes, filtered and dried in a Buchner funnel to give the title compound (1.43 g, 95%) as a tan solid. MS (ES)+ m/e 238 [M+H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.[CH:24]1(O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:24]1([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:14]3([C:12]([N:9]4[CH2:10][CH2:11][CH:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH2:8]4)=[O:13])[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(O)cc2)CC1
Reactant: OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(OC3CCCC3)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (40.0 mg, 0.000130 mol) in tetrahydrofuran were added cyclopentanol (29.4 μL, 0.000324 mol) diethyl azodicarboxylate (0.0511 mL, 0.000324 mol), and triphenylphosphine (85.0 mg, 0.000324 mol) at room temperature, and the reaction mixture was stirred overnight. The crude product was purified by prep-HPLC. LCMS: m/z 377.1 (M+H)+
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH2:10][C:11]#[N:12])=[CH:8][C:7]([F:13])=[CH:6][N:5]=1.Br[CH2:15][CH2:16]Cl>CN(C)C=O>[Cl:3][C:4]1[C:9]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15]2)=[CH:8][C:7]([F:13])=[CH:6][N:5]=1
Reactant: N#CCc1cc(F)cnc1Cl
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cc(F)cnc2Cl)CC1
Temperature: 50 °C
Yield: 60.7 %

Procedure:
Sodium hydride (60% in oil, 0.620 g, 15.5 mmol) was washed with hexanes (2×10 mL) under nitrogen. Dry dimethylformamide (5 mL) was added and the suspension cooled in an acetone/ice bath. A solution of 2-(2-chloro-5-fluoropyridin-3-yl)acetonitrile (0.571 g, 3.35 mmol) in dry dimethylformamide (10 mL) was added slowly and the reaction stirred for minutes. 1-Bromo-2-chloroethane (0.300 ml, 3.60 mmol) was added. After stirring in the cold bath for 5 minutes, the orange mixture was removed from the cold bath and heated at 50° C. After 45 minutes the mixture was cooled and carefully quenched by addition of saturated ammonium chloride (10 mL) then partitioned between 10% saturated ammonium chloride (200 mL) and ethyl acetate (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified using silica chromatography (hexane to ethyl acetate gradient) to give the desired 1-(2-chloro-5-fluoropyridin-3-yl)cyclopropanecarbonitrile (0.400 g, 2.034 mmol, 60.8% yield).