Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:35]>C(Cl)(Cl)Cl>[ClH:35].[ClH:35].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: c1cc(OC2CCCNCC2)c2nc(-c3nnc4ccccn34)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
To a solution of the product from Step B (0.40 g, 0.870 mmol) in CHCl3 (9 mL) was added hydrogen chloride (7.62 mL, 30.5 mmol, 4.0 M in dioxane) and the reaction was stirred at ambient temperature for 5 hours. The resulting yellow solid was removed by direct filtration and the solid was washed with Et2O and dried in vacuo to provide 0.296 g (72%) of the desired product as a yellow solid. MS ESI (+) m/z 360.1 (M+1) detected.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=O.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH2:7][CH2:6]3)=[CH:10][C:2]=2[O:1][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccccc1C(=O)c1cc2c(cc1O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2cc3c(cc2c1-c1ccccc1C)CCC3
Reaction time: 0.5 h

Procedure:
A solution of (6-hydroxy-2,3-dihydro-1H-inden-5-yl)(2-methylphenyl)methanone (2.0 g) in DMF (50 ml) was combined with sodium hydride (60%, in oil) (400 mg) with cooling in ice. After stirring at the same temperature for 30 minutes, the mixture was combined with ethyl bromoacetate (1 ml), and stirred for 1 hour. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was dissolved in toluene (50 ml), and combined with DBU (2 ml). The reaction solution was heated under reflux overnight, and then combined with water, and extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by a column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:3) to obtain a crude product of ethyl 3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-carboxylate. The resultant crude product of ester was dissolved in a solvent mixture of THF (50 ml) and methanol (30 ml), combined with a 1 N solution of sodium hydroxide (30 ml), and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was combined with water and extracted with ethyl acetate after acidifying with diluted hydrochloric acid. The extract was washed with water, and then dried over magnesium, and the solvent was distilled off under reduced pressure. The resultant residue was purified by recrystallization from ethyl acetate to obtain the title compound (0.9 g, yield: 39%) as a colorless crystal.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[O:12]=[CH:13][C:14]([Cl:17])([Cl:16])[Cl:15]>Cl(O)(=O)(=O)=O>[CH3:1][N:2]([CH:13]([OH:12])[C:14]([Cl:17])([Cl:16])[Cl:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CNC(=O)Nc1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN(C(=O)Nc1ccccc1)C(O)C(Cl)(Cl)Cl

Procedure:
1-methyl-3-phenyl urea (7.5 g, 0.05 mol) was reacted with 7.5 g (0.05 mol) of chloral without solvent. The mixture was shaken for a short period of time. After, 3 drops of perchloric acid were added and the mixture heated gently for a few minutes to give a homogenous viscous oil. Upon cooling, the product formed as a glass. The chemical analysis showed: %Cl, calculated 35.8, found 35.8; %N, calculated 9.4, found 8.0. The product is the fifth compound tabulated in Table I.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=[O:23].[Na+]>Cl>[CH3:14][C:13]1[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:23])[CH:7]=2)=[N:9][C:10]([NH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:11][CH:12]=1
Reactant: Cc1cnc(NC2CCOCC2)nc1-c1ccnc(F)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: Cc1cnc(NC2CCOCC2)nc1-c1cc[nH]c(=O)c1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
1M HCl (10 mL) was added to 4-(2-fluoropyridin-4-yl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.158 g, 0.548 mmol). The mixture was heated at reflux. After 2 hours, the cooled reaction mixture was neutralized with solid NaHCO3. The resulting solid was collected by vacuum filtration and dried to afford 4-(5-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (0.126 g, 0.440 mmol, 80.3% yield) as a solid.
Reaction SMILES: ClC1N=[C:6]([N:8](C)[C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH3:18])=[N:14][NH:15]3)=[CH:11][CH:10]=2)C=CN=1.C([O-])([O-])=O.[Cs+].[Cs+].ClC1C=C(C=CC=1)CBr>CN(C=O)C.C(OCC)(=O)C>[CH3:6][NH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH:17]=1)=[N:15][NH:14][C:13]=2[CH3:18]
Reactant: Cc1n[nH]c2cc(N(C)c3ccnc(Cl)n3)ccc12
Agent: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1ccc2c(C)[nH]nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-1H-indazol-6-amine (2 g, 7.31 mmol) was dissolved in DMF (15 ml), and Cs2CO3 (2 g, 14.6 mmol) and 3-chlorobenzyl bromide (1.25 ml, 9.5 mmol) were added at room temperature. Mixture was stirred at rt for overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated. The aqueous layer was thoroughly extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated to give 2-(3-chlorobenzyl)-N-2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine as an off-white solid. 1H NMR (300 MHz, d6DMSO) δ 7.94 (d, J=6.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.56 (d, J=1.3 Hz, 1H), 7.36-7.38 (m, 2H), 7.32 (br s, 1H), 7.16 (m, 1H), 6.91 (m, 1H), 6.28 (d, J=6.1 Hz, 1H), 5.65 (s, 2H), 3.42 (s, 3H), 2.63(s, 3H). MS (ES+, m/z) 398 (M+H).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][C:29]=2[OH:31])[N:24]=[CH:23][N:22]=1.O[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][C:29]=2[O:31][CH2:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:24]=[CH:23][N:22]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OC)cc(O)c23)c1
Reactant: OCCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OC)cc(OCCCN4CCOCC4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
Di-tert-butyl azodicarboxylate (0.208 g) was added dropwise to a stirred mixture of 4-(2-chloro-5-methoxyanilino)-5-hydroxy-7-methoxyquinazoline (0.2 g), 4-(3-hydroxypropyl)morpholine (Bull. Soc. Chim. Fr., 1962, 1117; 0.131 g), triphenylphosphine (0.237 g) and methylene chloride (3 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum to give the title compound (0.12 g); NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 3.1 (t, 2H), 3.3 (t, 2H), 3.5 (d, 2H), 3.68 (t, 2H), 3.8 (s, 3H), 4.0 (d, 2H), 4.02 (s, 3H), 4.6 (t, 2H), 6.93 (s, 1H), 7.05–7.15 (m, 2H), 7.5 (s, 1H), 7.57 (d, 1H), 8.87 (s, 1H); Mass Spectrum: M+H+ 459 and 461; Elemental Analysis: Found C, 60.0; H, 6.0; N, 12.1; C23H27ClN4O4 requires C, 60.19; H, 5.93; N, 12.2%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:29]3[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]4[CH2:41][C:40]([CH3:42])([CH3:43])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]4)=[CH:31][CH:30]=3)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3ccnc(OCc4ccccc4)c3c2)OC1(C)C
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: CN(c1ccc(-c2ccc3ccnc(OCc4ccccc4)c3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 94 %

Procedure:
The title compound (120 mg, 0.249 mmol, 94% yield) was prepared following GENERAL METHOD 1-4 for Suzuki reaction from 1-(benzyloxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (144 mg, 0.398 mmol) and (Intermediate 1-1, 75 mg, 0.265 mmol). LCMS Rt=0.57 min [Method Q]; MS (M+1)=482.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.81 (d, J=2.01 Hz, 1H), 8.39 (dd, J=8.41, 1.88 Hz, 1H), 7.99 (d, J=9.79 Hz, 1H), 7.76 (d, J=8.53 Hz, 1H), 7.72-7.74 (m, 1H), 7.46 (d, J=7.28 Hz, 1H), 7.26-7.37 (m, 5H), 7.24 (d, J=9.79 Hz, 1H), 6.76 (d, J=7.53 Hz, 1H), 5.29 (s, 2H), 3.01 (s, 3H), 1.71-1.78 (m, 2H), 1.61-1.70 (m, 2H), 1.44 (s, 6H), 1.29 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[F:10][C:4]1[CH:3]=[C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc(C=O)c(F)c1
Temperature: 100 °C
Yield: 71 %

Procedure:
4-Bromo-2-fluorobenzaldehyde (20.88 g, 102.87 mmol) and methyl acrylate (13.98 ml, 154.30 mmol) were taken up in thoroughly degassed DMA (150 nil) and tri-o-tolylphosphine (3.13 g, 10.29 mmol), palladium(II) acetate (1.155 g, 5.14 mmol) and triethylamine (28.7 ml, 205.74 mmol) added. The reaction was stirred and heated to 100° C. for 16 hours. More tri-o-tolylphosphine (3.13 g, 10.29 mmol) and palladium(II) acetate (1.155 g, 5.14 mmol) were added and the reaction mixture was heated to 110° C. for a further 2 hours. Water (1 L) was added and the reaction mixture extracted with DCM (2×500 ml). Combined organics were dried (MgSO4), filtered and evaporated to give a brown solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3-fluoro-4-formylphenyl)acrylate (15.20 g. 71.0%) as a yellow solid.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:5]2.[ClH:15]>O1CCOCC1.O>[OH:1][CH:2]1[CH:6]([Cl:15])[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:3]1
Reactant: Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CC(O)C(Cl)C1
Reaction time: 15 h

Procedure:
4.0 g of 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine are dissolved in 15 ml of dioxane, and the solution is treated with 50 ml of 6 N hydrochloric acid. The slightly exothermic reaction is kept at room temperature by means of a water bath, and the reaction mixture is stirred for 15 hours, then diluted with water and extracted 3 times with 100 ml of methylene chloride. The organic phase is washed with 0.1 N sodium hydroxide solution and then with aqueous sodium chloride solution, dried over sodium sulphate and then evaporated to dryness, first under a water pump vacuum and then under a high vacuum, 3-hydroxy-4-chloro-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine being obtained as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCCN1CCN(C)CC1
Product: CN1CCN(CCN(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-{methyl-[2-(4-methyl-piperazin-1-yl)-ethyl]-amino}-thiazol-4-one one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-[2-(4-methyl-piperazin-1-yl)-ethyl]-amine following General Procedure B.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[Na+].[OH:16][CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][C:20]([O-:22])=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.CCOCC>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3](=[O:4])[CH2:2][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH:17]([OH:16])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC(O)CCC(=O)[O-]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCC(O)CCC(=O)OCC(=O)c1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 26.6 %

Procedure:
A suspension of 20.00 g of 2-bromo-2′-acetonaphtone, 18.01 g of 4-hydroxy-undecanoic acid sodium salt, and 0.5 g of tetrabutylammonium bromide in 180 ml of dimethylformamide was stirred for 6 hours at 50° C. Then, the reaction mixture was diluted with ether and washed with water, 2N HCl, saturated sodium bicarbonate, and brine. Then, the mixture was dried, filtered, and evaporated to dryness. The resulting solid was purified by recrystallization to yield 7.92 g of colorless crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=O)=O.C(=[NH:52])(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:52][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: COc1ccc(COc2ccc3ccccc3c2-c2c(OS(=O)(=O)C(F)(F)F)ccc3ccccc23)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc3ccccc3c2-c2c(N)ccc3ccccc23)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A flask containing 2-(trifluoromethanesulfonyloxy)-2′-(4′-methoxybenzyloxy)-1,1′-binaphthyl (539 mg, 1.00 mmol), benzophenone imine (503 μL, 3.00 mmol), palladium acetate (11.2 mg, 0.0500 mmol), bis[2-(diphenylphosphino)phenyl]ether [DPE-phos] (40.4 mg, 0.0750 mmol), and triethylamine (70 μL) was purged with a gentle stream of argon for 20 minutes while stirring the mixture at room temperature. After this time, cesium carbonate (488 mg, 1.50 mmol) was added under a heavy stream of argon. The reaction mixture was then heated to 90° C. under an argon atmosphere for 32 hours. The reaction mixture was then cooled to room temperature and diluted with 30 mL of ethyl acetate. The organic solution was washed with a saturated aqueous sodium chloride solution (30 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was redissolved in 10 mL of tetrahydrofuran and 10 mL of ethanol to be treated with 2.0 mL of 2.0 M aqueous hydrochloric acid. The solution was stirred for 1 hour and then was diluted with 30 mL of aqueous 2.0 M sodium hydroxide. The organics were extracted with 40 mL of ethyl acetate. The organic layer was washed with 30 mL of a saturated aqueous sodium chloride solution. The organic solution was dried over anhydrous sodium sulfate and was concentrated in vacuo. The product was isolated as a white solid (369 mg, 91%) by crystallization from isopropanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N:3]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=C(C=Cc1ccnc(Br)c1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(Br)c2)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
1-(2-Bromo-pyridin-4-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.9 g, 8.9 mmol) prepared in Step 3, 2,4-difluorophenylhydrazine hydrochloride (2.4 g, 8.9 mmol), and piperidine (1.8 mL, 17.8 mmol) were added to ethanol (88.8 mL). The reaction mixture was stirred at 90° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 1.8 g of the titled compound as a yellow liquid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:28][CH2:29]Cl)[CH3:27].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][O:28][CH2:26][CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCOCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)COCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a mixture of diisopropylamine (2.1 mL, 15 mmol) and tetrahydrofuran (30 mL) was added dropwise n-butyl lithium (2.4 M n-hexane solution, 5.0 mL, 12 mmol) at −78° C., and then the reaction mixture was stirred for 30 minutes. Tributyltin hydride (3.3 mL, 12 mmol) was added dropwise to this mixture at −78° C., and then the reaction mixture was stirred for 40 minutes at 0° C. The reaction mixture was cooled to −78° C., after which ethoxymethyl chloride (1.1 mL, 12 mmol) was added dropwise to the reaction mixture. The reaction mixture was raised to room temperature, diethyl ether and an ammonium chloride aqueous solution were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride, after which the organic layer was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane:diethyl ether=30:1) to obtain the title compound (2.8 g, 66%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:24](=O)[CH3:25].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:24]1([CH3:25])[O:4][CH2:1][CH2:2][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cc(F)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2cc(F)ccc2Br)OCCO1
Yield: 60.2 %

Procedure:
Ethylene glycol (25.6 mL, 458 mmol) and p-toluenesulfonic acid (4.36 g, 22.9 g) were added to a solution of 1-(2-bromo-5-fluorophenyl)ethanone (10.5 g, 45.8 mmol) stirring in benzene (250 mL). The reaction mixture was equipped with a Dean Stark trap containing 4.0 angstrom molecular sieves and refluxed for 16 h. The reaction was transferred to a separatory funnel containing a 1:1 mixture of H2O and sat. NaHCO3 (aq) and extracted with EtOAc (3×100 mL). The combined organics were washed with H2O, brine, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography to give 2-(2-bromo-5-fluorophenyl)-2-methyl-1,3-dioxolane (7.20 g) in 58% yield. 1H NMR (CDCl3, 300 MHz) δ2.60 (s, 3 H) 4.02-4.20 (m, 4H), 6.85-6.90 (m, 1H), 7.29-7.33 (m, 1H), 7.48-7.56 (m, 1H).
Reaction SMILES: [NH4+:1].[Cl-].[Br:3][C:4]1[C:5]([F:22])=[CH:6][C:7]([F:21])=[C:8]([C:10]2([CH3:20])[NH:15][C:14](=S)[CH2:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:9]=1>N.CCO>[Br:3][C:4]1[C:5]([F:22])=[CH:6][C:7]([F:21])=[C:8]([C:10]2([CH3:20])[NH:15][C:14]([NH2:1])=[CH:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:9]=1
Reactant: CC1(c2cc(Br)c(F)cc2F)NC(=S)Cn2nccc21
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: CC1(c2cc(Br)c(F)cc2F)NC(N)=Cn2nccc21
Temperature: 85 °C
Yield: 78.7 %

Procedure:
NH4Cl (0.72 g, 13.4 mmol) was added to a stirred suspension of rac-4-(5-bromo-2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-thione (2.4 g, 6.7 mmol) in ammonia 2 M in EtOH (67 mL) and the mixture was heated at 85° C. for 18 hours. The solvent was removed in vacuo and the residue was suspended in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in AcOEt 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield rac-4-(5-bromo-2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-yl-amine (1.8 g, 78% yield) as a yellow solid.
Reaction SMILES: C1CC=CC=1.[OH:6][CH2:7][C:8]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9][CH3:10]>>[OH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH3:10]
Reactant: CC=C(CO)OCc1ccccc1
Agent: C1=CCC=C1
Product: CCC(=CO)OCc1ccccc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A thick walled, high pressure tube was charged with freshly cracked cyclopentadiene (0.841 g, 12.72 mmol) and 4-hydroxy-3-benzyloxy-2-butene (9.06 g, 50.92 mmol). The contents were degassed by bubbling nitrogen gas through the solution for 5 minutes. The tube was equipped with a magnetic stirring bar and fitted with a Teflon screw cap. The reaction tube was placed into a oil bath set at 185° C. and the starting materials were allowed to react for 48 hours. The tube was then taken out of the oil bath and allowed to cool to room temperature. The solution was transferred to a round bottom flask and the excess 1-Hydroxy-2-Benzyloxy-Butene distilled using vacuum distillation (105° C., 5 mmHg). The distillation yielded 3.48 grams of 1-Hydroxy-2-Benzyloxy-Butene. The remainder of the solution in the flask was treated with vacuum distillation yielding 1.924 grams (62%) of product at 189° C. (1 mmHg). The product was extracted using petroleum ether. The product was observed and it's identity confirmed by 1HNMR, 13CNMR, and HRMS.