Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH:22]([CH3:27])[CH2:23][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:28])[CH:4]=1)#[N:2].[OH-:29].[Na+].OO>CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH:22]([CH3:27])[CH2:23][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:28])[CH:4]=1)(=[O:29])[NH2:2]
Reactant: COc1ccc(-c2ccn(C(C)CC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccn(C(C)CC(=O)O)c2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of the crude 3-(2-(4-cyano-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid (120 mg) in DMSO (5 mL) was added a solution NaOH (26 mg, 0.65 mmol) in a mixture of water (0.5 mL) and H2O2 (0.33 mmol). After being stirred at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 26 mg of 3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid (yield 20% in two steps) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1.C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:26][CH:25]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3F)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Chloro-2-fluoro-benzenesulfonyl chloride (10.5 g) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (10.0 g) were added to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded the title compound as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 14.14 g (75%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2F)n1
Temperature: 150 °C
Yield: 45.1 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.279 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.069 g (45% yield) of pure product: MS (ES) m/z 496 (M+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH4+].[O-][Mo:13]([O-])(=O)=O.[O-][Mo]([O-])(=O)=O>O>[Mo:13].[CH3:2][N:3]([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[Mo](=O)([O-])[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)c1ccccc1
Product: [Mo]

Procedure:
N,N-dimethylaniline molybdate having a 2/1 molybdenum/N,N-dimethylaniline molar ratio was prepared in the presence of HCl as follows. 10 grams of N,N-dimethylaniline, 16.26 grams of a 37 wt.% aqueous HCl solution, and 250 ml water were dissolved together and heated to reflux in a 500 ml round-bottomed flask equipped with a water-cooled condenser. 28.05 grams of ammonium dimolybdate was dissolved in 52 ml hot water and then added to the first solution.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+].Br[C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29].Cl>CN1CCCN(C)C1=O.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(Br)C(N)=O
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C(N)=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reaction time: 18 h

Procedure:
4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg) was dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (1.5 ml) with stirring and sodium hydroxide (0.158 g) was added at ambient temperature and the mixture stirred for 15 minutes. 2-Bromo-2-methylpropanamide (0.5 g) was added and the mixture was stirred vigorously for 18 hours at ambient temperature under a water-free atmosphere, then further 2-bromo-2-methylpropanamide (0.15 g) was added and stirred for a further 24 hours. Water (3 ml) was added to the reaction mixture together with dilute hydrochloric acid (5M) to adjust the pH to 0. The suspension was added to water (60 ml) and the mixture left to stand for 18 hours at ambient temperature. The solid was collected by filtration, washed well with water and dried under high vacuum at 50° C. The solid was purified by preparative HPLC (reverse phase). Appropriate fractions were collected and combined and extracted with dichloromethane. Evaporation of the dichloromethane gave 2-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methylpropionamide, m.p. 227-228° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>O.C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:11]1[CH:10]=[CH:9][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][O:14][C:13]=2[CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(N)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(c1)OCC(c1ccccc1)=N2
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To potassium carbonate (63.89 g, 462 mmol) in water (300 mL) and CH2Cl2 (200 mL) is added 6-amino-m-cresol (10.0 g, 81.2 mmol) and tetra-n-butyl ammonium hydrogensulfate (0.139 g, 0.41 mmol). With vigorous stirring a solution of 2-bromoacetophenone (16.16 g, 81.2 mmol) is added dropwise over a period of 45 min. The mixture is allowed to stir overnight. The layers are then separated and the organic layer is washed with 1N NaOH (500 mL) and water (2×300 mL), dried over magnesium sulfate and concentrated. Column chromatography (400 g silica gel) using ethyl acetate/hexane (20/80) as eluent gave 8.96 g (49%) of 7-methyl-3-phenyl-2H-1,4-benzoxazine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]=2[CH:18]=1.CS(O[C@H:24]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:32]=2)[CH2:25]1)(=O)=O.[Cl-].[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([C@@H:28]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:32]=4)[CH2:27]3)[C:8]=2[CH:18]=1
Reactant: Fc1ccc2c(c1)Nc1ccccc1OC2
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)N([C@@H]1CCN(CCc3cccc(N4CCCC4)c3)C1)c1ccccc1OC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (88 mg, 2.2 mmol) was washed with hexane in argon gas stream and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 3-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (0.43 g, 2.0 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes. After stirring at 50° C. for 30 minutes, a solution of (S)-3-methanesulfonyloxy-1-(3-pyrrolidinophenethyl)pyrrolidine (0.34 g, 1.0 mmol) in dimethyl sulfoxide (4 ml) was added dropwise to the obtained solution, and they were stirred at 70° C. for 2 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (1:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-fluoro-5,11-dihydro-5-[1-(3-pyrrolidinophenethyl)pyrrolidin-3-yl]dibenzo[b,e]-[1,4]oxazepine in the form of a light yellow oily substance (0.19 g, 42%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].C([O-])(C)(C)C.[K+].[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32]I)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>CCCCCC.O1CCCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:32][CH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]1
Reactant: CCCCC[C@H]1CC[C@H](CCI)CC1
Reactant: Fc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCc2cccc(F)c2F)CC1
Reaction time: 0.17 h

Procedure:
A solution of 0.21 mol of n-butyllithium in 130 ml of hexane is added to a mixture of 0.25 mol of 1,2-difluorobenzene, 0.20 mol of potassium tert.-butanolate and 200 ml of tetrahydrofuran at -100° C. After the mixture has been stirred for 10 minutes, a mixture of 0.2 mol of 2-(trans-4-pentylcyclohexyl)-ethyl iodide, 0.2 mol of dimethylaminepropyleneurea and 50 ml of tetrahydrofuran is added at -90° C. After the mixture has been stirred at -40° C. for 1 hour, customary working up gives the ethane derivative of boiling point 135° C./0.5 mm Hg, in addition to a little 1,4-di-(2-trans-4-pentylcyclohexyl)-ethyl)-2,3-difluorobenzene as a by-product, of C 64° C. N 106.7° I.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:40])[C@@H:18]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:41].CO.[C:45]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][C:2]1([CH3:42])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:40])[C@@H:18]([N:27]([CH3:45])[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16]2)[C:3]1=[O:41]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)C(=O)N(C2CCN(C(=O)[C@H](CCc3ccccc3)NS(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CN([C@@H](CCc1ccccc1)C(=O)N1CCC(N2C(=O)C(C)(C)c3ccccc32)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a mixture of (S)—N-(1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)-2-nitrobenzenesulfonamide (1.26 g, 2.13 mmol, EXAMPLE 73, Step 1), methanol (519 microL, 12.8 mmol), triphenylphosphine (1.12 g, 4.27 mmol) in tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (2.2 mol/L toluene solution, 3.88 mL, 8.53 mmol) at room temperature. After 3 h, the mixture was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, gradient) to give a mixture of the title compound and triphenylphosphineoxide (3.30 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=3)=[CH:19][C:18]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1ccc(Br)cc1F
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(CC#N)c(F)c3)cc21

Procedure:
Prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (T. Alessi A. H. P. U.S. Pat. No. 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. A grey solid; mp 253-256° C. 1H-NMR(DMSO-d6) δ10.35 (s, 1H) 7.67-7.49 (m, 5H), 6.97 (d, 1H; J=8.6 Hz) 4.09 (s, 2H) 1.67 (s, 6H); MS [M−H]− m/z 309. Anal. Calc. For C18H15N2FO2.0.15H2O: C, 69.07; H, 4.93; N, 8.95. Found C, 69.27; H, 5.05; N, 8.50
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C)C=O.[CH:21]1([CH2:27][CH:28]([OH:43])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:39]([CH3:42])([CH3:41])[CH3:40])=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C1C=CN=CC=1)C.O>[CH:21]1([CH2:27][CH:28]([O:43][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:39]([CH3:41])([CH3:40])[CH3:42])=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)c1ccc(CC(O)CC2CCCCC2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
973 mg (6.46 mmol) of t-butyldimethylsilyl chloride, 0.90 ml (6.46 mmol) of triethylamine and 67 mg (0.55 mmol) of 4-(N,N-dimethylamino)pyridine were added to 10 ml of a dimethylformamide solution containing 1.74 g of 5-(3-cyclohexyl-2-hydroxypropyl)-2-t-butyl-1-nitrobenzene [prepared as described in step (i) above]. The mixture was then stirred for 1 hour and 20 minutes at room temperature, and then for 2.5 hours at 40° C. At the end of this time, the reaction solution was poured in water and extracted with a 3:1 by volume mixture of hexane and ethyl acetate. The organic layer was washed with dilute aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 75 g of silica gel. Elution with a 1:9 by volume mixture of diethyl ether and hexane afforded 2.22 g (yield 96% over the 2 steps) of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si](CC)(CC)CC)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C2C(=NC=CC=2)N(S(C2C=CC(C)=CC=2)(=O)=O)C=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](CC)(CC)c1cc2cc(Cl)cnc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Compound 41 (4.37 g, 0.0164 mol) was dissolved in THF. Molecular sieve (10 g of 3 A) was added followed by TBAF (32.75 mL, 0.0328). The reaction mixture was stirred for 5 h at rt. Diluted with ethyl acetate and washed several times with water, brine and the organic layer was dried and concentrated in vacuo to an oil that was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 02.3 g (90%) of the desired material 42. 1H NMR DMSO d6 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 6.5 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)=O.Cl.[NH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:13](=[N:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1
Reactant: Cc1cccc(C(=O)Cc2ccnc3ccc(Br)cc23)n1
Reactant: NN1CCCC1=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(C(Cc2ccnc3ccc(Br)cc23)=NN2CCCC2=O)n1
Yield: 69.6 %

Procedure:
Stir a mixture of 2-(6-bromo-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone (38.5 g, 113 mmol) and 1-aminopyrrolidinone hydrochloride (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g 4 Å unactivated sieves. Continue stirring an additional 13 h and add 10–15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid.
Reaction SMILES: Cl.C(OC1C=CC(C(N)=N)=CC=1)CCCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:35]([C:37]1[C:38](O)=[N:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:45][CH:44]=2)=[N:41][CH:42]=1)#[N:36].P(Cl)(Cl)([Cl:58])=O>C(O)C>[Cl:58][C:38]1[C:37]([C:35]#[N:36])=[CH:42][N:41]=[C:40]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:45][CH:44]=2)[N:39]=1
Reactant: CCCCCOc1ccc(-c2ncc(C#N)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCCCOc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-pentyloxybenzamidine hydrochloride with α-ethoxymethylene-α -cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-pentyloxyphenyl)-pyrimidine (melting point 213.5°-215.5° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-pentyloxyphenyl)-pyrimidine having a melting point of 140.5°-142.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH3:11][CH2:12][O:13][C:14]1[C:18](=O)[C:16](=[O:17])[C:15]=1[O:20]CC.CCCCCC.C(OCC)(=O)C>C(O)C>[CH2:12]([O:13][C:14]1[C:15](=[O:20])[C:16](=[O:17])[C:18]=1[NH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[CH3:11]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1ccc(N)c(O)c1
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O

Procedure:
A solution of 3-hydroxy-4-aminobenzonitrile (1.08 g, 0.008 mol) and diethyl squarate (1.19 ml, 0.008 mol) in dry ethanol (22 ml) was heated at 85° C. for two days. During the course of the reaction, a tan precipitate forms. TLC (1:1 hexane:ethyl acetate) indicates that no starting material is present. The solid is filtered through a Buchner funnel, washed with cold ethanol, and collected to give 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 1.19 g (0.0046 mol, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][NH:16][CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[BH3-][C:24]#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:24])[CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc3c(c2)CCNC3)c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN1CCc2cc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A 100 mL round bottom flask with a magnetic stirrer was charged with 258b (350 mg, 0.8 mmol), formaldehyde (37% aqueous soln, 4.1 mmol), NaBH3CN (150 mg, 2.4 mmol), ZnCl2 (170 mg, 1.2 mmol) in methanol (46 mL). The mixture was stirred for 16 h at room temperature. After this time, the mixture was concentrated under reduced pressure and 10% aqueous K2CO3 (25 mL). The desired product crashed out of this mixture and was filtered. Upon washing with diethyl ether (20 mL) afforded a 85% yield (240 mg) of 266a.
Reaction SMILES: C(S[C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=2)[C:7](=[O:16])[C:8]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:9]=2[N:10]=1)CC.[O-:29][CH2:30][CH3:31].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:30]([O:29][C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:7](=[O:16])[C:8]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:9]=2[N:10]=1)[CH3:31]
Reactant: CC[O-]
Reactant: CCCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (535 mg) in N,N-dimethylformamide (5 ml) was added sodium ethoxide (20% ethanol solution, 0.863 ml), and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was allowed to be cooled to room temperature, saturated brine was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (140 mg).