Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH2:6]2)=[CH2:2].B1C2CCCC1CCC2.C1C[O:25]CC1>>[OH:25][CH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH2:6]2
Reactant: C1CCOC1
Reactant: C=Cc1ccc2c(c1)CCCO2
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc2c(c1)CCCO2
Reaction time: 8 h
Yield: 24 %

Procedure:
A solution of the 6-vinylchroman intermediate (0.12 g, 0.27 mmol) in anhydrous THF (1 mL) was cooled to 0° C. and treated with 9-BBN (0.60 mL, 0.5 M in THF, 0.3 mmol). The reaction mixture was heated to reflux for 8 h. The reaction was quenched with water (1.5 mL) and treated with NaBO3·4H2O and the resulting slurry was stirred overnight. Diethyl ether (4 mL) and the reaction mixture were extracted with CH2Cl2 (2×20 mL). The organic layers were concentrated to a clear oil that was purified by silica gel chromatography eluting with ethyl acetate (50%, v/v) in hexane. This yielded the desired 6-(2-hydroxyethyl)chroman intermediate as a colorless oil (30 mg, 24%). 1H-NMR (CDCl3/TMS, ppm): 0.87 (m, 12H, 4a′-, 8a′-, 12a′-, 13′-CH3), 1.0-1.6 (m, 24H, 4′-, 8′-, 12′-CH, 1′-, 2′-, 3′-, 5′-, 6′-, 7′-, 9′-, 10′-, 11′-CH2, 2a-CH3), 1.81 (m, 2H, 3-CH2), 2.17, 2.24, 2.28 (3×s, 9H, 5a-, 7a-, 8a-CH3), 2.68 (t, J=6.8 Hz, 2H, 4-CH2), 3.01 (t, J=7.5 Hz, 2H, Ar-CH2), 3.74 (t, J=7.5 Hz, 2H, OCH2); 13C-NMR (CDCl3, ppm): 12.0, 15.1, 16.0 (5a-, 7a-, 8a-CH3), 19.6, 19.7 (CH3), 20.6, 21.0 (CH2), 22.6, 22.7 (CH3), 23.8 (2a-CH3), 24.4, 24.8 (CH2), 28.0 (CH), 31.2 (3-CH2), 32.7, 32.8 (CH), 37.3, 37.4, 37.5, 39.4, 40.0 (CH2), 62.2 (OCH2), 72.6 (2-C), 116.8, 122.3, 124.9, 132.4, 133.9 (aryl C), 150.1 (aryl C—O); HRMS (CI, m/z): 458.412154 (M+H+, Calc. for C31H54O2 458.412384).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C>C(Cl)Cl.[Zn]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)NCc1cncnc1-2
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A mixture of 68 g (0.2 mol) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 27 g of zinc dust and 250 ml of acetic acid in 600 ml of methylene chloride was stirred at -30° C. for 2 hr. The mixture was filtered over hyflo into a stirred mixture of 600 ml of concentrated ammonium hydroxide and 500 ml of ice. The methylene chloride solution was separated, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized from a mixture of methylene chloride and ether to give the product as a colorless solid. Recrystallization from a mixture of ether and methylene chloride gave the product as colorless needles, mp 169°-170° C.
Reaction SMILES: Cl[C:2]1(C#N)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[CH:5]2.[OH-:12].[K+]>CS(C)=O.O>[CH:3]12[CH2:9][CH2:8][CH:6]([CH:5]=[CH:4]1)[CH2:7][C:2]2=[O:12]
Reactant: N#CC1(Cl)CC2C=CC1CC2
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CC2C=CC1CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a stirred solution of 5-chloro-5-cyanobicyclo[2,2,2]oct-2-ene (65 g, 0.39 mol) (representing several runs of the foregoing procedure) in dimethyl sulfoxide (500 mL) was added potassium hydroxide (87.4 g, 1.56 mol) and water (30 mL). The resulting mixture was stirred at room temperature for 15 h, diluted with water (1000 mL) and extracted with ether (4×500 mL). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting with mixtures of diethyl ether (1% to 5%) in petroleum ether, to give bicyclo[2,2,2]oct-5-en-2-one (23.8 g. 50% yield) as a white solid, 1H NMR (300 MHz, CDCl3) δ 1.53˜1.84 (m, 4H), 2.01˜2.02 (m, 2H), 2.96˜2.99 (m, 1H), 3.11˜3.13 (m, 1H), 6.15˜6.21 (m, 1H), 6.43˜6.48 (m, 1H); GCMS (m/z): 122.
Reaction SMILES: C[CH:2]([N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1.[C:23](OCC)(=O)C>>[NH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH3:23])[CH2:2][N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21]
Reactant: CCOC(C)=O
Reactant: CC(c1cccc([N+](=O)[O-])c1)N1C(=O)c2ccccc2C1=O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Reaction time: 12 h

Procedure:
2-(Methyl-3-nitro-benzyl)-isoindole-1,3-dione (0.45 g, 1.52 mmol) was taken up in ethyl acetate in a Paar vessel and flushed with argon. Palladium on carbon (100 mg) was added and the argon atmosphere was replaced with hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen was then replaced with argon and the catalyst was removed by filtration through celite. The solvent was removed under reduced pressure to yield 0.40 g of the desired amine. C16H14N2O2 MS m/e=267.3 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([OH:22])=[O:21])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Yield: 96.7 %

Procedure:
A slurry of the product from part 8 (488 mg) and NaOH (226 mg) in 15 ml of methanol and 10 ml of water is stirred at 60° C. until a solution forms. The methanol is then evaporated in vacuo, and the remaining mixture is diluted with water. After adjusting the pH to 5–6 with 1N HCl, the solid is collected by filtration, washed with water and dried to give the title compound (450 mg) as a yellow solid, m.p. 187–90° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[O:5][C:6]=1[CH:7]([OH:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][C:32]=1[CH3:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:15][CH:7]([C:6]2[O:5][C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:33][C:32]=1[CH3:38]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(O)Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(Cc2ccccc2)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Yield: 45.1 %

Procedure:
To a solution of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanone (1.2 g, 3.5 mmol) in 50 mL MeOH at 0° C. is added LiBH4 (0.086 g, 3.50 mmol) portionwise. After gas evolution had ceased a tic indicated that the reaction is complete and 50 mL of NH4Cl (aq.) is added and the resultant solution extraxted with ethyl acetate (3×50 mL). The combined organics are dried (Na2SO4), filtered and concentrated under vacuo. The resultant crude oil is purified by flash column chromatography (10%–20%) ethyl acetate/hexane to provide 1.1 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol. To a solution of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol (0.50 g, 1.44 mmol), 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.28 g, 1.44 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.54 g, 2.16 mmol) in 15 mL toluene is added tributylphosphine (0.5 mL, 2.16 mmol). After 1 hr the volatiles are removed and the crude ester purified by flash column chromatography (10%–25%) ethyl acetate/hexane to provide 0.34 g (45%) of 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionic acid methyl ester as the racemate. The ester is separated by HPLC utilizing a chiral column with ethanol as the eluent. This enatiomerically pure ester (0.097 g, 0.18 mmol) is hydrolyzed in the usual manner 3 eq. 1N LiOH in 0.5 mL 3:2:1 solution of THF:MeOH:H2O to provide 0.09 g (93%) of the title compound. MS (M++1) 510.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:64][C:65]1[CH:66]=[C:67]([CH:69]=[CH:70][C:71]=1[CH3:72])[NH2:68]>>[F:64][C:65]1[CH:66]=[C:67]([NH:68][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:69]=[CH:70][C:71]=1[CH3:72]
Reactant: COC(=S)c1cc(Br)c(C)s1
Reactant: Cc1ccc(N)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: COC(=S)c1cc(Nc2ccc(C)c(F)c2)c(C)s1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
To an oven-dried glass vial with stir bar was added a mixture of 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a), 41 mg (10 mol %) of tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 70 mg (0.56 mmol) of 3-fluoro-4-methylaniline. The vial was transferred to a glove bag, flushed with dry argon and anhydrous toluene (0.9 mL) was added. The vial was capped with a Teflon-lined screw cap and heated at 100° C. for 48 h. To the cooled suspension was added ethyl acetate (4 mL), the mixture filtered (Celite) washing with ethyl acetate (2×2 mL), and the solvents removed in vacuo. The resulting residue was purified by silica gel preparative thin layer chromatography (10% Et2O in hexane) to afford 103 mg (78%) of the title compound as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ2.22 (d, 3H, J=1.6 Hz), 2.40 (s, 3H), 3.89 (s, 3H), 6.09 (s, 1H), 6.68 (m, 1H), 6.71 (s, 1H), 7.08 (m, 1H), 7.72 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1ccc(C(N)=O)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-2-nitrobenzamide 2 (1.0 g, 0.005 mol) in 20 mL dichloromethane cooled in an ice-bath was added aluminum chloride (2.0 g, 0.015 mol) portion wise. The resulting mixture was gradually warmed to room temperature and then refluxed for 6 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was added to water. The aqueous layer was separated and evaporated to dryness. The residue was dissolved in methyl tert-butyl ether, filtered and the filtrate was evaporated to give 4-hydroxy-2-nitrobenzamide 3. Colorless oil (0.7 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.07 (dd, J=2.4, 8.4 Hz, 1H); 7.32 (d, J=2.4 Hz, 1H); 7.45 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cl-].[NH+]1C=CC=CC=1.O>C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Yield: 101.9 %

Procedure:
3-Bromo-9-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ1, 1.50 g, 4.05 mmol) and pyridinium chloride (15.2 g, 32.5 eq.) were stirred at 160° C. for 12 hr under nitrogen atmosphere. After cooling, water and ethyl acetate were added and the resulting suspension was filtered. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were washed with MTBE to obtain the title compound (brown solid, 1.47 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:4][C:3]4[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=4[Cl:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: ClCc1ccc(Cl)cc1Cl
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3ccc(Cl)cc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 2,4-dichlorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a light yellow solid (75% yield). 1H NMR (300 MHz, CDCl3) δ 7.95-8.02, 7.44, 7.38, 7.23, 6.93, 3.70-3.77, 3.60-3.63, 3.54, 2.60-2.65, 1.50, 0.74, 0.45, 0.08. MS (ES+) m/z 434 (M+1).
Reaction SMILES: [Cl:1][C:2](Cl)([C:11]#[N:12])[CH2:3][S:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]#[N:8].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]([C:11]#[N:12])=[CH:3][S:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]#[N:8]
Reactant: N#CC(Cl)=C(Cl)SCC(Cl)(Cl)C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(Cl)=CSC(Cl)=C(Cl)C#N
Yield: 57.4 %

Procedure:
133 g of 1,2-dichloro-2-cyano-vinyl 2,2-dichloro-2-cyano-ethyl sulphide were dissolved in 350 ml of tetrahydrofuran, and 53.6 g of triethylamine were added dropwise at 5° to 10° C. The triethylamine hydrochloride which had precipitated out was filtered off with suction, the filtrate was concentrated and the residue was distilled (boiling point 120° to 145° C./2.5 mbar). 66.3 g of 1,2-dichloro-2-cyano-vinyl 2-chloro-2-cyano-vinyl sulphide were obtained as an oil, 1H-NMR: δ=7.1-7.4. A pure stereoisomer of melting point 58° to 60° C. crystallized out, 1H-NMR: δ=7.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].Cl>C(Cl)(=O)C>[Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: CCc1c(F)cccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1c(F)ccc(C(C)=O)c1Cl
Temperature: 40 °C
Yield: 38.5 %

Procedure:
A mixture of 1-chloro-2-ethyl-3-fluorobenzene (8.0 g) and anhydrous aluminum chloride (13.09 g) was stirred at 40° C., acetyl chloride (3 drops) was added thereto, and the mixture was stirred for 10 min. The mixture was cooled to room temperature, acetyl chloride (3.9 g) was added to the mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and 2 mol/L hydrochloric acid was added thereto. The mixture was extracted with methylene chloride (240 mL), washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) to give the title compound as a colorless oil (yield: 3.84 g).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][N:15]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Solvent: C1CCOC1
Product: CN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (350 mL), 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101j (10.0 g, 32.2 mmol), 2M methylamine solution in THF (113 mL, 225 mmol) and stirred at room temperature for 72 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was stirred with a mixture of ethyl acetate (75 mL) and 10% aqueous potassium carbonate (75 mL). The aqueous layer was separated and extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with 10% aqueous potassium carbonate (75 mL), followed by brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate concentrated under reduced pressure to afford 5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 101k in a 97% yield (5.70 g) as a yellow solid: 1H NMR (300 MHz, CDCl3) d 6.62 (s, 1H), 4.28 (t, 2H, J=5.4 Hz), 3.67 (s, 2H), 2.95 (t, 2H, J=5.4 Hz), 2.52 (s, 3H); MS (ESI+) m/z 183.0 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:35])[C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2)=[O:25]>>[CH3:22][N:23]([CH3:35])[C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH:30]=[CH:29]2)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Reactant: CN(C)C(=O)c1ccc2[nH]ccc2c1
Product: CN(C)C(=O)c1ccc2c(ccn2-c2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-1-carboxylate (intermediate-5) and N,N-dimethyl-1H-indole-5-carboxamide (intermediate-12).
Reaction SMILES: C[Al](C)C.[CH:5]1([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23]C)=O)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH2:42])[NH:40][N:41]=2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1(C)C=CC=CC=1>[CH:5]1([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[N:16]=[CH:17][C:18]([C:21]([NH:42][C:39]4[NH:40][N:41]=[C:37]([CH2:36][CH2:35][C:29]5[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:27]([O:26][CH3:25])[CH:28]=5)[CH:38]=4)=[O:23])=[CH:19][N:20]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCCN(C3CC3)CC2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C5CC5)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 1.5 %

Procedure:
Trimethylaluminium (1.402 ml, 2.80 mmol) was added dropwise to a stirred suspension of methyl 2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (310 mg, 1.12 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (277 mg, 1.12 mmol) in toluene (5.61 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (8.00 mg, 1%) as a cream solid. Some impure fractions were combined and concentrated to dryness and purified by crystallisation from MeCN to afford the title compound (51 mg, 9%) as a cream solid.
Reaction SMILES: [N:1]1([C:6]2[CH:22]=[CH:21][C:9]([CH2:10][CH:11]3[C:16](=[O:17])[O:15]C(C)(C)[O:13][C:12]3=[O:20])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1>O.FC(F)(F)C(O)=O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([C:12]([OH:20])=[O:13])[C:16]([OH:17])=[O:15])=[CH:21][CH:22]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC1(C)OC(=O)C(Cc2ccc(-n3cncn3)cc2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)C(Cc1ccc(-n2cncn2)cc1)C(=O)O
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
5-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.0 g, 33.2 mmol, Intermediate 45, step b) was dissolved in a mixture of water (30 mL) and trifluoroacetic acid (50 mL). The mixture was heated to 65° C. After 2.5 hours, the mixture was allowed to cool to 23° C. Water and trifluoroacetic acid were removed by rotary evaporation at 45° C. Toluene (100 mL) was added to the residue then the mixture was concentrated by rotary evaporation at 45° C. Tetrahydrofuran (100 mL) and 6 M aqueous hydrochloric acid solution (28 mL) was added to the residue in sequence. The resulting heterogeneous mixture was stirred at 23° C. After 10 minutes, the mixture was concentrated by rotary evaporation at 45° C. Tetrahydrofuran (100 mL) was added to the residue and the mixture concentrated by rotary evaporation at 45° C. Toluene (100 mL) was added to the residue and the mixture concentrated by rotary evaporation at 45° C. The resulting white solid was dried under vacuum at 40° C. The solid product was used directly in the next step without further purification.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH2:6]([O:8][C:9](=[O:13])[CH2:10][NH:11][CH3:12])[CH3:7].C(O[C:17](=[C:20]([C:23]#[N:24])[C:21]#[N:22])[CH2:18][CH3:19])C.Cl>C(O)C>[CH2:6]([O:8][C:9]([C:10]1[N:11]([CH3:12])[C:17]([CH2:18][CH3:19])=[C:20]([C:21]#[N:22])[C:23]=1[NH2:24])=[O:13])[CH3:7]
Reactant: CCOC(=O)CNC
Reactant: CCOC(CC)=C(C#N)C#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N)c(C#N)c(CC)n1C
Temperature: 15 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Alternatively the title compound may be prepared by the following procedure. Charge ethanol (3.40 L, denatured with 0.5% toluene) to a 22 L 3-neck reaction flask equipped with a mechanical stirrer, condenser, addition funnel and cooling bath. Cool the ethanol to 8° C. and add sodium ethoxide (805 grams, 11.35 mol) portion-wise over 20 minutes. In a separate flask, combine sarcosine ethyl ester hydrochloride (697 g, 4.54 mol), 2-(1-ethoxy-propylidene)-malononitrile (681 grams, 4.54 mol, prepared in preparation 35) and ethanol (3.0 L) and stir to dissolve the solids. Add the resulting solution to the 22 L flask over 33 minutes while maintaining about 11 C. Maintain the reaction mixture between 10-20° C. for 3.5 hours. Stir the mixture at room temperature overnight, then cool to 1° C. Adjust the pH to 7.0 by adding 1 N HCl (6.58 L) and stir the resulting suspension at 0-5° C. for 3 hours. Collect the precipitate by filtration, rinse the filter cake with deionized water (1.0 L) and vacuum-dry at 40° C., to afford the title compound in 66.7% yield. Mass spectrum (m/e): 222.4 (M+1).
Reaction SMILES: [OH:1][C:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)([CH2:5][CH3:6])[CH2:3][CH3:4].C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1>[OH:1][C:2]([C:7]1[S:8][C:9]([C:17]([OH:19])=[O:18])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH2:5][CH3:6]
Reactant: CCC(O)(CC)c1cccs1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(C(=O)O)s1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a −78° C. mixture of 2-(3-hydroxy-3-pentyl)thiophene (0.34 g, 2.0 mmol) in THF (2 ml) is added of 1.6 M n-butyllithium in Hex (2.75 ml, 4.4 mmol). The mixture is allowed to warm to RT and powderized dry ice (CO2) is added. After one h, the mixture is partitioned between diethyl ether and 1N NaHCO3. The aqueous layer is washed with ether, acidified with conc. HCl and extracted with ether. The organic layer is Na2SO4 dried, filtered, and concentrated to give the title compound (0.236 g, 53%).