Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][C:13](=[O:16])[C:12]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:19]1[CH:24]=[C:23]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][C:13](=[O:16])[C:12]=3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1COc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 98.9 %

Procedure:
Cesium carbonate (612 mg, 1.88 mmol) was added to a solution of 5-bromobenzofuran-3(2H)-one (200 mg, 0.939 mmol), (3-fluorophenyl)boronic acid (263 mg, 1.88 mmol) and toluene (20 mL) in a 50 mL Schlenk tube. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.01 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient), to afford 212 mg (99%) of 5-(3-fluorophenyl)benzofuran-3(2H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH2:16]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:16]([N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:6](=[O:8])[C:5]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CNCC(C)C
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)CN(CC(C)C)C(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 64.8 %

Procedure:
To a slurry of 106.5 g of 2,6-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 133.2 g of diisobutylamine. Next 44.9 g of phosphorus oxychloride was added dropwise at such a rate to maintain the temperature below 40° C. The mixture was heated to 50° C. for 12 hrs and poured into 500 ml of aqueous 5% NaHCO3 solution with stirring. The organic layer was separated, washed with 500 ml water, and the toluene removed under reduced pressure. The remaining solid was recrystallized from hot ethanol to give 105.2 g of N,N-diisobutyl-2,6-dinitrobenzamide, a yellow solid, mp 97°-99° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:15]1([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 600 mg, 3.00 mmol) in dry DCM (10 ml) was added cyclobutanone (CAS number 1191-95-3; 248 μl, 3.30 mmol), acetic acid (257 μl, 4.49 mmol) and molecular sieves. The reaction was then stirred at room temperature for 1 hour. To this was then added sodium triacetoxyborohydride (952 mg, 4.49 mmol) and the reaction was allowed to stir at room temperature for 17 hours. The reaction was basified by the addition of 2M NaOH (aq) and the organics were extracted DCM, filtered through a hydrophobic frit and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:29](O)[CH2:30][OH:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:17])[O:31][CH2:30][CH2:29][O:18]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CC(C)=O)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 1-(4-nitro-benzyl)-5-(2-oxo-propyl)-1H-indole-2-carboxylic acid ethyl ester (1.91 g, 5.03 mmol), ethylene glycol (406 mg, 0.365 ml, 6.54 mmol), and p-toluenesulfonic acid monohydrate (110 mg, 0.58 mmol) in toluene (50 ml) was heated to about 150° C. under a Dean-Stark trap under nitrogen for two hours. The solution was cooled, diluted with ethyl acetate, washed with dilute sodium bicarbonate and brine, dried over sodium sulfate, filtered, and dried under reduced pressure to give the title compound in crude form (2.4 g), which was reacted without further purification.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=O.[CH:30]([NH2:32])=[S:31].[OH-].[Na+]>O1CCOCC1>[F:29][C:24]1[CH:23]=[C:22]([C:20]2[N:32]=[CH:30][S:31][CH:19]=2)[CH:27]=[CH:26][C:25]=1[OH:28]
Reactant: NC=S
Reactant: O=C(CBr)c1ccc(O)c(F)c1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: C1COCCO1
Product: Oc1ccc(-c2cscn2)cc1F
Temperature: 25 °C
Yield: 83 %

Procedure:
To a stirred solution of phosphorus pentasulfide (8.6 g, 19.3 mmol) in dioxane (53 ml) was added formamide (5.2 g, 115.5 mmol), and the mixture was heated at reflux temperature for 2 hours. The mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (3.02 g, 12.98 mmol) in dioxane (50 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:3) to give title compound (2.11 g, 83% yield).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>N1C=CC=CC=1.Cl>[CH:1]1([C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)C1CCCC1
Yield: 48.1 %

Procedure:
Cyclopentanoyl chloride (946 mg, 7.14 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (1.0 g, 7.14 mmol) in pyridine (10 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The reaction mixture was cooled then stirred in 2N hydrochloric acid (100 ml) and the resulting solid collected by suction filtration. Purification by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane, yielded 2-(N-cyclopentanoyl)amino-5-nitropyrimidine (812 mg, 48% yield) as an beige solid:
Reaction SMILES: Cl.N1C=CC=C([CH:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=O)=[C:11]3[CH2:10][S:9]2)C=1.[NH2:19]C1C=C(C=CC=1Cl)C(C1C=CC=CC=1)=O.C>O1CCOCC1.C(#N)C.C(N(CC)CC)C>[CH2:10]1[S:9][CH2:8][N:12]2[CH:13]=[CH:14][C:15]([C:16]([NH2:19])=[O:18])=[C:11]12
Reactant: O=C(O)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cc(C(=O)c2ccccc2)ccc1Cl
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccn2c1CSC2
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 124.3 %

Procedure:
Hydrochloride of the acid chloride derived from (+)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylic acid (5.4 g) is added, at a temperature between 60° and 62° C., to a solution of 3-amino-4-chlorobenzophenone (4.1 g) and triethylamine (3.65 g) in dioxane (80 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 5 hours and 40 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in methylene chloride (250 cc). The solution obtained is washed twice with distilled water (200 cc in total), with an aqueous 2N sodium hydroxide solution (100 cc) and then 3 times with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 45° C. A crude product (8.3 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (30 cc in total) and twice with diethyl ether (60 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. (+)-N-(2-chloro-5-benzoylphenyl)-3- pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.7 g) in the form of cream-coloured crystals, m.p. 154° C., is thereby obtained.
Reaction SMILES: [S:1]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14]Cl)[S:2][CH2:3][CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].[N:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>CN1C(=O)CCC1.CC(C)=O>[Cl-:8].[Cl-:8].[S:1]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14][N+:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[S:2][CH2:3][CH2:4][NH:5][C:6](=[O:9])[CH2:7][N+:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1
Reactant: Cc1ccncc1
Reactant: O=C(CCl)NCCSSCCNC(=O)CCl
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc[n+](CC(=O)NCCSSCCNC(=O)C[n+]2ccc(C)cc2)cc1
Product: [Cl-]
Reaction time: 19 h

Procedure:
6.1 g of N,N′-(disulphanediyldiethane-2,1-diyl)bis(2-chloroacetamide) and 4.5 g of 4-picoline are dissolved in 50 ml of NMP and brought to 80° C. for 19 h. After cooling of the mixture via successive precipitations in acetone and drying under vacuum, 9.2 g of salts are recovered. The analyses show that the product is in conformity. 1H NMR (400 MHz, D2O): 2.61 (s, 6H), 2.82 (t, 4H), 3.56 (t, 4H), 5.31 (s, 4H), 7.85 (d, 4H), 8.51 (d, 4H).
Reaction SMILES: [CH3:1][CH:2]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:16]=[O:17].N1C=CC=CC=1.Cl>CO.CCOCC>[CH3:1][C:2]([CH2:16][OH:17])([C:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=O
Reactant: COC(=O)C(C)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(C)(CO)C(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 98.1 %

Procedure:
Into a 5 liter RBF is placed 1000 g (4.37 mole) of methyl 2-methyl-3-(4-chlorophenyl)-3-keto-propanoate, 157 g (5.25 mole) of paraformaldehyde, 1000 ml of pyridine, and 50 g of Triton B (40% in MeOH). The resulting mixture was heated 50° C. for 2 hours. After cooling to room temperature, the reaction mixture was transferred to a 12 liter separatory funnel and 1.5 liters of ether and 2 kgs of ice are added. The mixture is slowly acidified by 1.0 liters of conc HCl and the organic phase is separated, washed with 2 liters of brine and dried over MgSO4. On concentration, it affords 1100 g (100%) of a red oil, methyl 2-methyl-2-hydroxymethyl-3-(4-chlorophenyl)-3-keto-propanoate. NMR data was consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].[NH:30]1CCCCC1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:27]4[NH:30][C:24](=[O:29])[NH:25][C:26]4=[O:28])=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Reactant: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (39 mg, 0.133 mmol) in EtOH was added 2,4-thiazolidinedione (16 mg, 0.133 mmol) and piperidine (13 μL, 0.133 mmol). The mixture was heated at 70° C. The solid formed was isolated by filtration and air dried to yield 5-((5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=394)
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([CH:8]([OH:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[CH:20]([OH:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24].[H-].[Na+].[H][H].[CH3:36][Si:37](Cl)([CH3:39])[CH3:38]>C1COCC1>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([CH:8]([O:19][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:9]([F:17])([F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[CH:20]([O:31][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:21]([F:29])([F:30])[C:22]([F:27])([F:28])[C:23]([F:26])([F:24])[F:25]
Reactant: OC(c1[nH]c(C(O)C(F)(F)C(F)(F)C(F)(F)F)c(Br)c1Br)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [H][H]
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(c1[nH]c(C(O[Si](C)(C)C)C(F)(F)C(F)(F)C(F)(F)F)c(Br)c1Br)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
3,4-Dibromo-2,5-bis(2',2',3',3',4',4',4'-heptafluoro-1'-hydroxybutyl)pyrrole (1 mmol, 0.62 g) was dissolved in 25 ml of dry THF and transferred to a cooled (0° C.) suspension of sodium hydride (2.0 mmol, 0.048 g) in 100 mL of THF. When hydrogen evolution ceased (after 2 hours) trimethylsilyl chloride (2 mmol, 0.218 g) was added by syringe. The mixture was stirred at room temperature overnight before the solvent was removed in vacuo. The remaining residue was partitioned between 10% sodium bicarbonate solution and ether and the organic layer was dried over magnesium sulfate, filtered and evaporated to leave a brown oil. The product was purified by chromatography on silica gel using hexane as eluant. The product was the first material off the column (rf =0.5) The fractions containing this spot were evaporated to leave a colorless oil which solidified upon cooling under vacuum to leave 3,4-dibromo-2,5-bis(2',2',3',3',4',4',4'-heptafluoro-1'-trimethylsilyloxy-butyl)pyrrole as white needles. (380 mg, 50% yield) 1H NMR (360 MHz, CDCl3) 8.84 (broad s, 1 H); 5.30 (dd, 2 H, J1=19.5, J2=1.0); 0.06 (s, 18 H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:35][C:36]1[CH:37]=[C:38]([CH:54]=[CH:55][C:56]=1[CH3:57])[C:39]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:43]=1)=[O:40].ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([NH:35][C:36]2[CH:37]=[C:38]([CH:54]=[CH:55][C:56]=2[CH3:57])[C:39]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[CH:43]=2)=[O:40])=[O:31])[CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 0 °C
Reaction time: 40 h
Yield: 51.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g) was added to a stirred mixture of 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid (0.307 g), 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide (0.312 g), 1-hydroxybenztriazole (0.202 g) and DMF (5 ml) which had been cooled to 0° C. The resultant reaction mixture was stirred at ambient temperature for 40 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using a 3:1 mixture of isohexane and ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.31 g); NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 2.12 (m, 2H), 2.27 (s, 3H), 3 08 (t, 4H), 3.37 (m, 3H), 3.57 (m, 1H), 3.74 (t, 4H), 5.05 (m, 1H), 6.67 (d, 1H), 7.17 (m, 2H), 7.3 (d, 1H), 7.42 (m, 3H), 7.52 (s, 1H), 7.57 (d, 1H), 7.78 (d, 1H), 7.93 (s, 1H), 10.0 (s, 1H), 10.01 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:17][O:18][C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(F)cc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(4-fluorophenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-].C(OCC)(=O)C.O>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([O:1][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:7][CH2:6]3)[C:9]3[N:10]([N:33]=[CH:34][CH:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.63 g) and rhodium acetate (dimer, 0.12 g) in methylene chloride (20 mL) was added dropwise a solution of ethyl diazoacetate (2.6 g) in methylene chloride (10 mL), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.17 g, 70%).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:17][C:16]=3[CH:15]=2)[CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].Br[C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][N:44]=1>>[NH:45]1[C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43]([C:18]2[N:19]=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:21]3[S:22][C:14]([CH2:13][N:10]4[CH2:9][CH2:8][N:7]([C:2]([CH3:1])([CH3:6])[C:3]([NH2:5])=[O:4])[CH2:12][CH2:11]4)=[CH:15][C:16]=3[N:17]=2)=[N:44]1
Reactant: Brc1n[nH]c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4n[nH]c5ccccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure G for Stille coupling, 2-methyl-2-(4-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide and 3-bromo-1H-indazole were reacted to give 215. LCMS m/z: 521.6 (MH+)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([F:13])([F:12])[F:11])=[O:7].[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[I-].[Na+].C(N(CC)CC)C>O.C(OCC)(=O)C>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]([C:5]1[CH:4]=[C:3]([CH:18]=[CH:17][CH:16]=1)[CH2:2][N:22]1[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]1)=[O:7])([CH3:15])[CH3:14]
Reactant: CC(C)(NC(=O)c1cccc(CCl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C(F)(F)F)c2)CC1
Yield: 97.6 %

Procedure:
3-(Chloromethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (3.10 mmol, 868 mg), tert-butyl piperazine-1-carboxylate (3.10 mmol, 578 mg), sodium iodide (3.10 mmol, 465 mg) and triethylamine (3.10 mmol, 0.433 mL) were all combined in actetonitrile (28 ml) and heated to reflux for 2 hours. After this time the reaction mixture was allowed to cool and ethyl acetate and water were added. The organic layer was separated, dried and concentrated under vacuum to yield the title compound (1.3 g).