Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13](NCC)C1C=CC=CC=1.CC#N.O.CC#N>O>[CH2:1]([N:8]([CH2:12][CH3:13])[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)Cl
Reactant: CCNCc1ccccc1
Solvent: CC#N
Solvent: O
Product: CCN(Cc1ccccc1)C(=O)Cl

Procedure:
The title compound is prepared analogously as described for benzyl-methyl-carbamoyl chloride from benzyl ethylamine. MS (LC-MS): [M+H]+=198.1. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.12 min.
Reaction SMILES: [OH:1][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][CH:8]([O:10]C2CCCCO2)[CH:9]=1)=[O:3].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[O:1][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:3]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)CC1=CC(OC2CCCCO2)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC1=CC(O)CC1=O)Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 g of 2-Hydroxycarbonylmethyl-4-tetrahydropyranyloxy-2-cyclopenten-1-one (21 mmol) obtained from Example 5, 2-naphthol (4.7 g, 32 mmol), dichloromethane (50 ml), and 0.2 g 4-(dimethylamine)pyridine were added together to a 50 ml dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7 g, 34 mmol). The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 20 ml of diluted hydrochloride solution, water, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The crude product was dissolved in 30 ml acetone and 6 ml water, further added with 0.3 g p-toluenesulfonic acid and stirred overnight. Upon completion of the reaction, acetone was evaporated and the reaction mixture was diluted with ethyl acetate and washed with an aqueous sodium bicarbonate solution and a brine solution. The organic liquid was subjected to the previous work-up procedure, including dehydration, filtration, and evaporation, and purification by chromatography on silica gel to obtain the title compound as white solid. MP: 81° C. (4.2 g, 71%) 1H-NMR (CDCl3/TMS): δ 7.82 (m,2H), 7.78 (d, 1H), 7.55 (m,2H), 7.46 (m,2H), 7.21 (dd, 1H), 5.04 (m, 1H), 3.56 (s, 2H), 2.89 (dd, 1H), 2.38 (dd, 1H), 1.60 (brs, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:19]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[C:8](=[O:10])[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:13]([OH:14])=[C:12]([C:15]([CH3:16])([CH3:18])[CH3:17])[CH:11]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNCCCC
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a stirred solution of 25 grams (0.1 mole) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 12.9 grams (0.1 mole) of di-n-butylamine in 100 milliliters of dry tetrahydrofuran was added dropwise a solution of 20.6 grams (0.1 mole) of dicyclohexylcarbodiimide in 75 milliliters of dry tetrahydrofuran. The mixture was stirred for several hours and the white solid (dicyclohexyl urea) was filtered off and discarded. Evaporation of the filtrate gave a white solid, which was recrystallized from 1:1 benzene-hexane to give N,N-di-n-butyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 94°-95°C. When tested by the procedure of Example 2, the sample containing this compound lasted 1000 hours, about 3.3 times as long as the control.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[C:10]3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1>>[N:11]1[C:10]2=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:9]2=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:18]2[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2nc(N3CCNCC3)nc-2cc1
Reactant: Nc1ccnc(Cl)n1
Product: Nc1ccnc(N2CCN(c3nc4cccccc-4n3)CC2)n1

Procedure:
Similarly, by condensing 2-(1-piperazinyl)cycloheptimidazole with 2-chloro-4-aminopyrimidine, there was obtained 2-[4-(2-cycloheptimidazolyl)-1-piperazinyl]-4-pyrimidinamine (I: R1, R2, R4 and R5 =H; R3 =2-cycloheptimidazolyl; and n=1) as the di-(Z)-2-butenedioate salt: mp 205°-208° C. (crystallized from methanol-diethyl ether); and Anal. Calcd for C16H17N7.2C4H4O4 : C, 53.43% H, 4.63% N, 18.18% and Found: C, 53.66% H, 4.81% N, 18.34%.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1B(O)O)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:14]1[N:15]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:12][C:13]=1[C:24]([O:26][CH3:27])=[O:25])[CH3:29]
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: CCOc1cccc(F)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cccc(F)c1-c1nc(-c2c(C)nn3ccccc23)sc1C(=O)OC
Temperature: 90 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
A suspension of Methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (306 mg, 0.72 mmol) obtained in Example 13-B(ii), (2-ethoxy-6-fluorophenyl)boronic acid (262 mg, 1.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (80 mg, 0.098 mmol) and cesium carbonate (850 mg, 2.6 mmol) in DME (20 mL), was added water (2 mL), and the mixture was stirred at 90° C. for 5 h. The reaction mixture was allowed to cool to rt, water (200 mL) was added, and the mixture was extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate, insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=50/50→100/0) to give the title compound (295 mg, 100%) as a yellow solid. 1H-NMR (DMSO-d6, 300 MHz) δ 1.07-1.23 (3H, m), 2.70 (3H, s), 3.72 (3H, s), 3.97-4.13 (2H, m), 6.85-7.61 (5H, m), 8.29 (1H, d, J=8.9 Hz), 8.80 (1H, d, J=6.8 Hz).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CS(Cl)(=O)=O.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]([C:23]2[C:24]([F:33])=[CH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:17]=1>N1C=CC=CC=1>[NH2:22][C:20]1[N:21]=[C:16]([NH:15][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[N:17]=[C:18]([C:23]2[C:24]([F:33])=[CH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:19]=1
Reactant: Nc1nc(N)nc(-c2cc3ccccc3cc2F)n1
Reactant: O=C(O)c1cccnc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2cc3ccccc3cc2F)n1

Procedure:
Nicotinic acid (0.58 gram) was dissolved in 10 ml of pyridine, 0.27 gram of methanesulfonyl chloride was added thereto, the mixture was heated to reflux for thirty minutes, 0.5 gram of 2,4-diamino-6-(2-fluoro-3-naphthyl)-s-triazine was added, and the mixture was heated to reflux for four hours. After the reaction was completed, pyridine was evaporated, water was added to the residue, the resulting separated mass was subjected to a column chromatography using 100 grams of silica gel, and eluted with ethyl acetate-benzene (9:1) to afford 2-amino-4-nicotinoylamino-6-(2-fluoro-3-naphthyl)-s-triazine, colourless crystals, melting point 230° to 235° C. (with decomposition). The yield was 0.35 gram.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:29])[CH3:28])[C:6]2[O:10][C:9]([C:11]3[CH:25]=[CH:24][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:26]=1)#[N:2].C(N(CC)CC)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=1>CO>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:21]2[CH2:22][CH2:23][CH:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[O:10][C:6]5[C:5]([CH:27]([CH3:29])[CH3:28])=[CH:4][C:3]([C:1]#[N:2])=[CH:26][C:7]=5[N:8]=4)=[CH:25][CH:24]=3)[CH2:20]2)=[CH:40][CH:39]=1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNC4)cc3)oc12
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(Cc5ccc(Br)cc5)C4)cc3)oc12
Temperature: 150 °C
Yield: 67.2 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(pyrrolidin-3-ylmethyl)benzamide (78 mg) in 2 ml of methanol was added 558 μl of triethylamine and 50 mg of 1-bromo-4-(bromomethyl)benzene. The solution was heated to 150° C. via microwave for 30 min, cooled, and purified via column chromatography on a Biotage Horizon 40M column eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 6 column volumes at 100% ethyl acetate to provide the title compound (75 mg, 68%). Mass spectrum (ESI) 559.0 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=8.5 Hz, 2H), 7.96 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.52 (s, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 3.52 (m, 3H), 2.98 (td, J=9.1, 2.9, 1H), 2.76 (d, J=9.6 Hz, 1H), 2.58 (m, 2H), 2.32 (m, 1H), 2.14 (m, 1H), 1.68 (m, 1H), 1.48 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Cl)c2Cl)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4cccc(Cl)c4Cl)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,3-dichloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 70) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-2-[4-(2,3-dichloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a light brown solid as a mixture of diastereomers (1.28 g, 88%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:12][CH:14]1[CH2:15][O:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1cccc(O)c1
Product: CC(C)(C)c1cccc(OCC2CO2)c1

Procedure:
The title compound was prepared from 3-tert-butyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH2:15][S:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:23]=1[Cl:29].CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=1[O:18][CH:13]([CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][S:16][CH3:17]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CSCCC(O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CSCCC(Oc1cccc(Cl)c1Cl)C1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(1-Hydroxy-3-methylsulfanylpropyl)pyrrolidine-1-carboxylic acid t-butyl ester (49 mg, 180 μmol) was dissolved in DMF (550 μL). 60% NaH in oil (60:40, NaH:mineral oil, 8.5 mg, 210 μmol) was slowly added, and the mixture was stirred for 15 minutes at room temperature. 1,2-Dichloro-3-fluorobenzene (62 μL, 530 μmol) was added, and the resulting mixture was heated at 90° C. for 24 hours. The reaction was quenched with MeOH, and DMF/MeOH was removed in vacuo. The product was dissolved in 1.25M HCl in EtOH (1.4 mL, 1.8 mmol) and stirred overnight at room temperature. The product was then purified by preparative HPLC to yield the title compound as a mixture of all 4 stereoisomers (R,R, R,S, S,S, and S,R) as mono-TFA salts (20 mg, 100% purity). MS m/z: [M+H] calcd for C14H19Cl2NOS, 320.06. found 320.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:35]1([NH:45]N)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:36]4[C:35](=[C:44]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]5=[CH:38][CH:37]=4)[NH:45][C:22]=3[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc([N+](=O)[O-])cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 574.7 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[I-:15].[Na+]>C(#N)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:5]([O:4][CH2:3][CH2:2][I:15])=[O:6])=[CH:9][CH:10]=1
Reactant: [I-]
Reactant: Cc1ccc(SC(=O)OCCCl)cc1
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(SC(=O)OCCI)cc1
Temperature: 50 °C

Procedure:
A 50 mL, three-neck, round-bottomed flask equipped with a magnetic stir bar, a reflux condenser, an internal thermometer, and a nitrogen inlet was charged with chloro-ester D1 (2 g, 8 mmol) and sodium iodide (1.8 g, 12 mmol) in acetonitrile (10 mL). The resulting slurry was warmed to 50° C. for 36 hours. The reaction mixture was cooled to room temperature and inorganic solids were removed by filtration. The clear organic phase was concentrated to give a viscous oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E4b as a viscous-oil (1 g, ˜30% yield). 1H NMR (CDCl3, 400 MHz): δ 2.31 (d, J=5.6 Hz, 3H), 2.47 (s, 3H), 6.80 (q, J=6 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H).
Reaction SMILES: [C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][S:11][CH:12]=[C:8]2[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][S:11][CH:12]=[C:8]2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2cscc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1Cc2cscc2C1

Procedure:
Dissolve 5-(carboethoxy)-2,4,5,6-tetrahydrocyclopenta[c]thiophene (6.68 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 5-(carboxy)-2,4,5,6-tetrahydrocyclopenta[c]thiophene.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10](OC)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[OH-].[Na+]>ClCCl>[CH:2]1([N:8]2[C:10](=[O:15])[CH2:11][C:12]([CH3:14])=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CC(C)=O
Reactant: NNC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1=NN(C2CCCCC2)C(=O)C1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture solution of 39.88 g (0.265 mol) of cyclohexylhydrazine HCl salt in 28.57 mL (0.265 mol) of methyl acetoacetate was heated for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, dichloromethane was added to this mixture and the mixture was neutralized by 2N—NaOH aqueous solution. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was treated with hexane to give crystalline and the crystalline was collected by filtration to give 33.84 g (71%) of the title compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4SC)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>ClCCl.O>[C:42]([NH:46][C:17]1[N:16]2[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]=3)=[C:21]2[CH:20]=[CH:19][N:18]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Reactant: CC(C)(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Nc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (40 mg, 0.095 mmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (12 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 1 hour. t-Butylamine (3 mL) was added and heated to reflux for 3 hours. The reaction was allowed to cool and diluted with water. The mixture was extracted with ethyl acetate and the organic phase washed with brine before being concentrated under vacuum. The residue was purified by silica gel chromatography eluting with SO/5 acetone in dichloromethane to yield a 1:1 mixture of starting material and product. The residue was dissolved in dichloromethane (2 mL) and 3-chloroperoxybenzoic acid (18 mg, 0.21 mmol) was added. The mixture was stirred for 2 hours and then t-butylamine (3 mL) was added. The reaction mixture was stirred for 3 hours, diluted with water, extracted with ethyl acetate, washed with brine, concentrated, and the residue purified by silica gel chromatography eluting with 5% acetone in dichloromethane to yield N-(tert-butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine (6 mg, 14%), 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.72 (d, 1H), 7.60 (dd, 2H), 7.47 (d, 1H), 7.13 (t, 2H), 6.42 (s, 1H), 6.25 (d, 1H), 5.14 (bs, 1H), 4.28 (m, 1H), 2.04 (m, 2H), 1.45–1.78 (m, 15H). MS m/z 446 (M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=3[F:23])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].ClC(Cl)C.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][C:16]=3[F:23])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(-c3ccc(C=O)cc3F)n2n1
Reactant: CC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCNc1ccc2ncc(-c3ccc(CNC(C)(C)C)cc3F)n2n1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A mixture of 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-3-fluoro-benzaldehyde (120 mg, 0.40 mmol) and dichloroethane (DCE, 4 mL) was treated with tert-butyl amine (0.050 mL, 0.50 mmol) and the resulting reaction mixture was maintained at RT for 20 min. The reaction was then treated with sodium triacetoxyborohydride (170 mg, 0.80 mmol) and the resulting mixture was maintained until LCMS indicated complete consumption of the aldehyde. The reaction was quenched with saturated aqueous sodium bicarbonate, the layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by reverse phase HPLC to afford butyl-{3-[4-(tert-butylamino-methyl)-2-fluoro-phenyl]-imidazo[1,2-b]pyridazin-6-yl}-amine (98 mg, 67%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.21 (dd, J=12.3, 1.5 Hz, 1H), 7.93 (dd, J=8.0, 1.7 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=9.7 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 6.68 (d, J=9.7 Hz, 1H), 4.02 (s, 2H), 3.34 (t, J=7.2 Hz, 2H), 1.84 (s, 1H), 1.61-1.71 (m, 2H), 1.39-1.50 (m, 2H), 1.32 (s, 9H), 1.25-1.30 (m, 1H), 0.91-0.99 (m, 3H); LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H29FN5 370.2].
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1ccccc1Br
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-bromophenyl(2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:27])=[C:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([C:8]1[NH:9][C:10]2[CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:4](=[O:3])[C:6]=2[C:7]=1[CH3:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1c(CCCNCCN(C)C)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Temperature: 25 °C
Yield: 71.3 %

Procedure:
5-[3-(2-Dimethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 23a (5.85 g, 13.8 mmol) was dissolved in 130 ml of toluene under stirring, and added slowly with a solution of trimethyl aluminum in toluene (12 ml, 2 mol/L, 24 mmol) to the solution under an argon atmosphere. Upon the completion of the addition, the reaction mixture was stirred for 10 minutes at room temperature until no white smoke was released, and heated to reflux for 3 hours in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with ice water. After the reaction system was naturally cooled down to room temperature, the mixture was added with hydrochloric acid solution (50 ml, 2 mol/L) and stirred for 10 minutes. The mixture was adjusted to pH 9 with aqueous sodium hydroxide solution (2 mol/L), and extracted with dichloromethane (50 ml×4). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 23b (3.3 g, yield 71.4%) as a yellow solid.