Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]3=[O:26])[CH2:12][CH2:13][C:7]=2[C:6]([O:27]C)=[C:5]([O:29][CH3:30])[C:4]=1[O:31][CH3:32].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:32][O:31][C:4]1[C:3](=[O:2])[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]3=[O:26])[CH2:12][CH2:13][C:7]=2[C:6](=[O:27])[C:5]=1[O:29][CH3:30]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCn1c(=O)ccc3ccccc31)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCn3c(=O)ccc4ccccc43)CC2)C1=O
Reaction time: 0.25 h
Yield: 54.4 %

Procedure:
To a mixture of 1-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethyl]-1,2-dihydro-2-quinolinone (612 mg), pyridine-2,6-dicarboxylic acid (702 mg), THF (12 ml), and, water (6 ml) was added an water (6 ml) solution of CAN (3.07 g) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography(hexane to hexane:ethyl acetate=8:1) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (310 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13][F:14])=[CH:4][C:3]=1[F:19].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:25]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]1)[N:9]([CH2:12][CH2:13][F:14])[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1cn(CCF)c2cc(Cl)c(F)cc2c1=O
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CCN1
Yield: 33.8 %

Procedure:
A mixture of 1.50 g of 7-chloro-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.60 g of 2-methylpiperazine and 8 ml of pyridine was heated for 11 hours under reflux. The solvent of the reaction mixture was evaporated and the residue was dissolved in hot water. After cooling of the solution, the precipitate was filtered and recrystallized from ethanol to give 0.62 g of the title compound as colorless needles, M.p. 226°-227° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][O:11][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][CH:7]=1
Reactant: CC(CCO)c1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(CCOC1CCCCO1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To the solution of 3-(4-bromophenyl)butan-1-ol (791 mg, 3.47 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (437 mg, 5.2 mmol) and p-toluenesulfonic acid (60 mg, 0.347 m mol), the solution was stirred for 12 hours at room temperature, then the solution was washed with water and dried with sodium sulfate, concentrated to give 2-(3-(4-bromophenyl)butoxy)-tetrahydro-2H-pyran (1.05 g, 97%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11]([CH3:19])[C:9]=2[N:10]=1.[ClH:20]>O.P(=O)(O)(O)O.Cl[Cu]>[Cl:20][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11]([CH3:19])[C:9]=2[N:10]=1
Reactant: COC(=O)c1ccc2sc(N)nc2c1C
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Solvent: O
Product: COC(=O)c1ccc2sc(Cl)nc2c1C
Temperature: 100 °C

Procedure:
At −8° C., a solution of 9.3 g of NaNO2 (0.14 mol) in 10 ml of water was added dropwise to a solution of 5 g of methyl 2-amino-4-methylbenzothiazole-5-carboxylate (0.02 mol) in 150 ml of phosphoric acid. At 5° C., a solution of 3 g of CuCl and 12 ml of conc. HCl was then added dropwise. The reaction mixture was heated to 100° C. After cooling, the residue was filtered off with suction, washed with water and dried. The product was purified by silica gel column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:19]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(C1C(C)=C2C(NC3C=CC(SC4N(C)C=CN=4)=C(Cl)C=3)=C(C#N)C=NN2C=1)=O)C.CN(C=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:31][N:30]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cn1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cn3)c2c1C
Yield: 50.8 %

Procedure:
Compound 429 (21 mg, 51%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (26 mg, 0.1 mmol) and 429C (210 mg, 1.0 mmol) by a route analogous to that used for the preparation of compound 426, DMF (1 ml) was used as solvent instead of THF. 429 is a yellow solid and has a retention time of 6.24 min (standard LC1 method, 8 min run). MS Found: (M+H)+=414.2
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([C:11]1[CH:10]=[CH:9][C:3]([NH:4][C:5]([O:7][CH3:8])=[O:6])=[C:2]([F:1])[CH:12]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)CBr
Reactant: COC(=O)Nc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Nc1ccc(C(C)(C)C)cc1F
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 111.2 %

Procedure:
2-Fluoro-N-methoxycarbonylaniline (500 mg, 3.11 mmol) was dissolved in methylene chloride (20 mL) to prepare a solution. Anhydrous aluminum chloride (986 mg, 7.77 mmol) was added to the solution, and the mixture was stirred at 40° C. for 20 min. Thereafter, the reaction solution was cooled to room temperature. A solution of isobutyl bromide (1.60 mL, 15.5 mmol) in a methylene chloride solution (6 mL) was added dropwise to the cooled reaction mixture while bubbling argon gas over a period of 10 min. The mixture was stirred for one hr. Water was added thereto, followed by separation of an organic layer. The organic layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was then removed from the dried organic layer by distillation to give 779 mg of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as a crude product. The crude product was further subjected to separation and purification by column chromatography on silica gel to give 433 mg of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline (yield 64.0%, 4-t-butyl form: 5-t-butyl form=88:12).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:37])[C:22]([C:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]=3[CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12]C.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]([CH3:37])[C:22]([C:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]=3[CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[CH:18][CH:19]=2)[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OC)c(Br)c2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
Boron tribromide (31.8 mL of a 1 M solution in methylene chloride; 31.8 mmol) was added under nitrogen dropwise over 30 minutes to a solution of N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (5.37 g, 10.6 mmol), prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 1.5 h. At ice bath temperature-water was added dropwise. The aqueous layer was separated and extracted two times with methylene chloride. The extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (5.26 g, 100%) as a light brown foam, MS (ESI) m/z 492 [M+H]+. Elemental Analysis for C27H26BrNO3. Calc'd: C, 65.86; H, 5.32; N, 2.84. Found: C, 64.98; H, 5.15; N, 2.63.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][C:10]1(Cl)[C:15](=[O:16])[CH2:14][CH2:13][CH2:12]C1=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH:12]=1
Reactant: COC(=O)CCCC#CCC1(Cl)C(=O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COC(=O)CCCC#CCC1=CCCC1=O

Procedure:
To a solution of 7-(1-chloro-2,6-dioxocyclohexyl)-5-heptynoic acid methyl ester (23.6 g), described in Example 14, in xylene (250 ml) is added powdered sodium carbonate (11.8 g) and the mixture stirred and heated at refluxed for 16 hr. After cooling the mixture is washed with water to neutral, dried over magnesium sulfate, and the solvent evaporated to give the crude cyclopentenone ester. Distillation of the crude ester at 0.6 mm Hg affords 7-(5-oxocyclopent-1-enyl)-5-heptynoic acid methyl ester, b.p. 142° - 156° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:27]([O-])=O.[Na+]>Cl.CN1CCCC1=O.O>[CH2:20]([O:19][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:3]2[C:2]3[N:1]=[N:27][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)=[CH:15][CH:14]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1snc(-c2ccc(NC(=O)OCc3ccccc3)cc2)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccc(-c2nsc3c(=O)[nH]nnc23)cc1)OCc1ccccc1
Yield: 71.6 %

Procedure:
22.5 g of 4-amino-3-(4-benzyloxyformamidophenyl)-5-isothiazolecarboxamide in 25 ml of concentrated hydrochloric acid and 150 ml of N-methylpyrrolidone were cooled in an ice-bath and stirred during the addition of 4.89 g of sodium nitrite dissolved in 20 ml of water. After 0.5 hour 150 ml of water were added and the resulting precipitate was filtered off, washed with water, dried in vacuo and recrystallized from ethyl acetate to yield 16.6 g of 7-(4-benzyloxyformamidophenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one of melting point 190°-191° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=O)[NH:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=[S:22])[NH:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=C1CC(=S)Nc2ccccc2N1Cc1ccccc1
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A solution of 1-benzyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (160 mg, 0.60 mmol) and P2S5 (140 mg, 0.63 mmol) in 20 mL of pyridine was heated to reflux and stirred for 1 h under N2 atmosphere. The solvent was evaporated in vacuo, the residue was purified by prep-TLC (DCM:MeOH=50:1) to give 1-benzyl-4-thioxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (50 mg, 30%). 1H NMR (300 MHz, DMSO): δ 3.74 (q, J=12.3 Hz, J=12.3 Hz, 1H), 5.12 (q, J=15.6 Hz, J=15.9 Hz, 1H), 7.03-7.06 (m, 2H), 7.17-7.27 (m, 6H), 7.48 (d, J=7.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:45]([C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1)[NH2:46].C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([NH:46][NH:45][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2ccccc12)Cc1cc(F)ccc1F
Reaction time: 0.29 h

Procedure:
A solution of 158 mg (0.5 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1), 96 mg (0.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 89 mg (0.63 mmol based on 95% purity) of 1-hydroxybenzotriazole (HOBT) in 4 mL of anhydrous dichloromethane was stirred at room temperature in a stoppered flask. After 15-20 min, this solution was added dropwise by syringe through a septum to a second solution of 95.5 mg (0.6 mmol) of 1-hydrazinoisoquinoline (Intermediate 8) and 0.261 mL (194 mg, 1.5 mmol) of N,N-diisopropylethylamine in 2 mL of anhydrous dichloromethane and 2 mL of anhydrous DMF. Stirring under nitrogen was continued for 4 h. The solution was then concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with more 5% citric acid, then with water, and finally with saturated sodium carbonate aqueous solution. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue contained the title compound along with some material that had already undergone ring closure. LC-MS 457 (M+1 for title compound), 439 (M+1 for ring-closed product).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][N:13]([CH:16]=[CH2:17])[C:12]1=[O:18])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][N:13]([CH:16]=[CH2:17])[C:12]1=[O:18]
Reactant: C=CN1CCC(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CN1CCC(CCO)C1=O
Temperature: 25 °C

Procedure:
To a stirred and ice-cold solution of 3-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-vinylpyrrolidin-2-one (TBSE-VP) (269 mg; 1.0 mmol) in dry tetrahydrofuran (10 mL) was dropwise added a 1.0 m solution of tetrabutylammonium fluoride (2.0 mL; 2.0 mmol; 2.0 equiv.) under an argon atmosphere. Upon completion of the addition the reaction mixture was left stirring at 0° C. for 5 min, allowed to warm to ambient temperature over 5 min and left stirring for another 40 min. The reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL) and the aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Column chromatography (ethyl acetate) afforded the target compound (135 mg; 0.87 mmol; 87%) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9]C(=O)C)=[CH:4][C:3]=1[CH3:13].[OH-].[K+]>O1CCOCC1>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:13]
Reactant: CC(=O)Oc1cc(C)c(F)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(O)cc(C)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetic acid 4-fluoro-3,5-dimethyl-phenyl ester in 10 mL dioxane was added 10 mL aqueous 5% KOH at 25° C. After being stirred for 30 min at 25° C., the reaction was quenched by the addition of 12 mL of 1M aqueous HCl. The mixture was extracted ethyl acetate (3×30 mL) and the combined organic layers were washed with brine (2×30 mL). The solution was dried over Na2SO4 before being concentrated under reduced pressure. The product was isolated by silica gel chromatography to afford the title compound 987 mg, as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1.C=O.[CH2:24](P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:12]2=[CH:13][C:14]3[O:18][CH2:17][O:16][C:15]=3[CH:19]=[C:20]2[O:21][CH2:24]1
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C1Nc2c(F)cccc2C1c1cc2c(cc1O)OCO2
Agent: C=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
A solution of 7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (2.00 g, 7.00 mmol) and paraformaldehyde (2.10 g, 61.0 mmol) in THF (50 mL) was degassed by bubbling through argon for one hour, followed by the slow addition of lithium diisopropylamide (48.8 mL, freshly made 0.50 M solution, 25 mmol) at −78° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonium chloride (50.0 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in anhydrous ethyl acetate (50 mL) followed by the addition of tributylphosphine (2.10 mL, 8.00 mmol) and di-tert-butyl azodicarboxylate (1.90 g, 8.00 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride (30.0 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in methanol (70.0 mL) followed by the addition of saturated sodium bicarbonate solution (30.0 mL). The resulted mixture was refluxed at 100° C. for one hour. After cooling down to ambient temperature, the mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.27 g, 17%): 1H NMR (300 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.17-7.08 (m, 1H), 7.00-6.88 (m, 2H), 6.64 (s, 1H), 6.33 (s, 1H), 5.92-5.85 (m, 2H), 4.74 (d, 1H), 4.62 (d, 1H).
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].[CH:7](OCC)(OCC)[O:8][CH2:9][CH3:10]>C(OC(=O)C)(=O)C>[CH2:9]([O:8]/[CH:7]=[C:3](\[C:2](=[O:1])[CH3:6])/[C:4]#[N:5])[CH3:10]
Reactant: CC(=O)CC#N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C(/C#N)C(C)=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
Into a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-oxobutanenitrile (compound 257.1, 16.0 g, 193 mmol) in acetic anhydride (48 mL). Triethyl orthoformate (96 mL, 577 mmol) was added and the reaction was stirred for 2 h at 130° C., then concentrated under reduced pressure to obtain the title compound as a red solid (10 g, 37%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Al+3].Cl>CC(O)C>[CH3:2][CH:1]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
Acetophenone (0.601 g) was dissolved in 15 ml of 2-propanol, 2.04 g of aluminum triisopropoxide was added, and the mixture was stirred at 25° C. for 4 hours. After hydrolysis with 1 N hydrochloric acid, the mixture was extracted with ethyl acetate. Concentration gave 0.564 g of an oil, which was analyzed by HPLC (conversion 0.6%, yield 0.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([OH:13])[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:12][CH2:11][CH:10]=[O:13])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1CCC=O
Temperature: 45 °C
Reaction time: 16 h

Procedure:
A mixture of 1.00 g (3.39 mmol) of 4-bromo-1-iodo-2-methylbenzene, 0.58 g (10.00 mmol) of allyl alcohol, 0.69 g (8.20 mmol) of sodium bicarbonate, 0.92 g (3.30 mmol) of tetrabutylammonium chloride, and 22 mg (0.10 mmol) of palladium (II) acetate in 5 mL of DMF were stirred for 16 hours at 45° C. under argon. The reaction mixture was diluted with EtOAc, and the organic phase was washed with water, dried over magnesium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, PE/EtOAc 4:1). Yield: 0.60 (78% of theoretical); C10H11BrO (M=227.098); calc.: molpeak (M+H)+: 226/228 (Br); found: molpeak (M+H)+: 226/228 (Br); Rf value: 0.45 (silica gel, PE/EtOAc 4:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH3:14])([CH2:12][CH3:13])[C:10]#[N:11])=[N:6][CH:7]=1.[CH3:15][C:16]1[CH:17]=[C:18]([NH:31][C:32]2[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:14][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[CH:19]=[C:18]([NH:31][C:32]3[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=3)[CH:17]=[C:16]([CH3:15])[CH:21]=2)=[CH:7][N:6]=1)([CH2:12][CH3:13])[C:10]#[N:11]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCC(C)(C#N)Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCC(C)(C#N)Nc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 100 °C

Procedure:
Argon was bubbled through a mixture of 2-[(5-bromopyridin-2-yl)amino]-2-methylbutanenitrile (327 mg, 1.29 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (488 mg, 1.29 mmol), and sodium carbonate (2 M, 1.28 mL, 2.57 mmol) in 2-methyl-THF (6.43 mL) for ˜5 minutes. PdCl2(dppf)-dichloromethane adduct (52.5 mg, 0.064 mmol) was added and the reaction was heated to 100° C. overnight. The cooled reaction mixture was diluted with water and extracted dichloromethane (3×). The organic layer was concentrated under reduced pressure and purified by reverse phase chromatography to yield 2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}butanenitrile. MS APCI calc'd for C22H22F3N6 [M+H]+ 427. found 427. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.3, 1H), 8.44 (s, 1H), 7.85-7.68 (m, 1H), 7.31 (t, J=17.9, 2H), 7.14-6.93 (m, 2H), 6.76 (d, J=9.3, 1H), 2.41 (s, 3H), 2.17-2.03 (m, 2H), 1.62 (s, 3H), 0.93 (t, J=7.3, 3H).