Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].[N:12]1[CH:17]=CC=NN=1>CCO.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:12][CH:17]=[N:11]2
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: c1cnnnc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=c1[nH]cnc2cccc(Cl)c12
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 6-chloro anthranilic acid (2.12 g, 12.3 mmol) and triazine (1.0 g, 12.3 mmol) in EtOH (40 mL) containing piperidine (3 drops) was heated under reflux with stirring for 8 h. On cooling crystals formed, which were filtered to yield 5-chloroquinazolin-4-one (1.55 g, 70%).
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O.C(OCC)(=O)C>[N:10]1([CH2:9][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CC(C)Br
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 3-bromobutanoate (6.0 mL, 42 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added piperidine (8.0 mL, 80 mmol) and the mixture was warmed to room temperature then stirred 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-piperidin-1-ylbutanoate (6.8 g, 81% yield) as brown oil. MS (EI) for C11H21NO2: 200 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C(P(CCCC)CCCC)CCC.[CH3:34][O:35][C:36](=[O:50])[CH:37]([CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39].CCCCCCC>C1C=CC=CC=1>[CH3:41][O:40][C:38](=[O:39])[CH:37]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:12][CH2:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:47][CH:48]=1)[C:36]([O:35][CH3:34])=[O:50]
Reactant: COc1ccc(C(=CCO)c2ccc(OC)cc2)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: COC(=O)C(Cc1ccc(OCC=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
Under a nitrogen atmosphere, 3,3-bis-(4-methoxy-phenyl)-prop-2-en-1-ol (500 mg, 1.95 mmol), tributylphosphine (424 (mg, 2.1 mmol) and 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (464 mg, 1.95 mmol) were successively dissolved in dry benzene (50 mL). Solid azodicarboxylic dipiperidide (ADDP) (530 mg, 2.1 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and di hydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified by chromatography eluting with heptane/ethylacetate (4:1) to give 150 mg (16%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:73]([SH:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:73]([S:80][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.98 g, 34.47 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (8.86 g, 68.94 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.48 g, 36.19 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to warm to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (white solid, 12.44 g, 86.0% yield). 1H NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 7.79 (dd, 1H), 7.41 (dd, 1H), 7.24 (m, 5H), 7.18 (m, 1H), 7.00 (m, 1H), 6.87 (m, 1H), 4.08 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:14]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)Cc1ccccc1OC
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(C)=O)ccc1O
Reaction time: 5 h

Procedure:
36 g of methyl 2-methoxy-benzeneacetate and 15.7 g of acetyl chloride are dissolved in 100 ml of methylene chloride, the resultant solution then being added dropwise to a suspension of 100 g of aluminum chloride in 300 ml methylene chloride. The solution is boiled for 5 hours, poured onto ice water and filtered. The crystals are washed with water and methylene chloride.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.Cl>CS(C)=O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: N#Cc1ccc(F)cc1
Reactant: Nc1cncnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To 20 ml of dimethyl sulfoxide was added 2.8 g of potassium tert-butoxide. After stirring at room temperature for 30 minutes, 1.9 g of 5-aminopyrimidine was added thereto, followed by stirring at room temperature for 30 minutes. To the solution was added 1.21 g of 4-fluorobenzonitrile, and the mixture was stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. The reaction mixture was poured into ice-water, neutralized with hydrochloric acid. The resulting crystals were collected by filtration and dissolved in acetone. Any insoluble matter was removed by filtration, and the solvent was removed by distillation. The resulting crystals were washed with ethyl ether to obtain 1.04 g of 5-[(4-cyanophenyl)amino]pyrimidine.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1B(O)O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: COc1ccc(B(O)O)c(OC)c1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nc(C)cnc2C)c(OC)c1
Temperature: 75 °C

Procedure:
A mixture of 3-chloro-2,5-dimethyl-pyrazine (283 mg, 2.0 mmol), 2,4-dimethoxyphenylboronic acid (455 mg, 2.5 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 5 mol %) in DME (12 mL) and sodium carbonate (1M in water, 4 mL) is heated at 75° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, and washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (25% ethyl acetate in hexanes) yields 3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazine as an oil MS: 245.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:32]1([CH2:38][CH2:39][CH2:40][C:41]#[CH:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH:11]1([CH2:10][CH2:9][C:8]([N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:42]#[C:41][CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:31][CH:30]=2)=[O:16])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Reactant: C#CCCCc1ccccc1
Product: CC1(C)OC(=O)c2ccc(N(Cc3ccc(C#CCCCc4ccccc4)cc3)C(=O)CCC3CCCC3)cc2O1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 5-phenyl-1-pentyne as a yellow oil (54%). M+ (ESI): 550.2. HPLC, Rt: 5.96 min (Purity: 94.9%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.I[CH2:30][CH2:31][CH3:32].Cl.CN(C)C1C=CC([C@@H]2CCN(CC)C[C@H]2COC2C=CC(C(F)(F)F)=CC=2)=CC=1>C(O)C>[ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][N:13]([CH2:30][CH2:31][CH3:32])[CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCCI
Agent: CCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Solvent: CCO
Product: CCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Yield: 37 %

Procedure:
Preparation from (41) (0.35 g) and 1-iodopropane (0.2 ml) by heating in ethanol of 70° C. for 8 h, as described for compound (42). Yield 37%, m.p. 224.2°-225.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[C-:10]#[N:11].[Na+]>C(C#N)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.[Cu]I>[C:10]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1)#[N:11]
Reactant: OCc1ccc(Br)cn1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1ccc(CO)nc1
Temperature: 110 °C
Yield: 47.8 %

Procedure:
(5-Bromo-pyridin-2-yl)-methanol (1.0 g), NaCN (521 mg), Pd(PPh3)4 (612 mg), and CuI (200 mg) were taken up in degassed EtCN and heated at 110° C. (4 h). The solution was partitioned between EtOAc and 10% NH4OH (aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave a yellow solid. Purification via flash chromatography (1/2 hexanes/EtOAc, SiO2) gave 341 mg (48%) of (5-cyano-pyridin-2-yl)-methanol as a white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:23][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=1)[NH:14][C:13]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:20][CH:21]=1)=[CH:12]2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Product: CS(=O)(=O)Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1

Procedure:
Cyclopentyl-[2-(4-aminophenyl)-5-chloro-1H-indol-7-yl]-amine prepared in Example 82 and methanesulfonylchloride were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N:21]1C2C(=CC=CC=2)C=C[CH:22]=1>CN(C)C=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([F:20])([F:19])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:22]#[N:21])([F:18])[F:17])=[CH:2][CH:7]=1
Reactant: Fc1ccc(C(F)(F)C(F)(F)c2ccccc2)c(Br)c1
Reactant: c1ccc2ncccc2c1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(F)(F)C(F)(F)c1ccc(F)cc1

Procedure:
A mixture of 8.5 g. (0.024 mole) of 2-bromo-4,α,α,α',α'-pentafluorobibenzyl, 6.4 g. of cuprous cyanide, 75 ml. of dry quinoline and 7.5 ml. of dry dimethylformamide is stirred and heated to refluxing for 34 hours. The precipitate is removed from the cooled mixture by filtration and washed with a mixture of benzene and ether. Solvents are evaporated from the filtrate under reduced pressure leaving the product as an oily black solid. Sublimation at 80°C. and 0.05 mm. yields light brown solid, m.p. 90°-93°C. Purification is effected by column chromatography on 300 g. of silica, the product being eluted with benzene-hexane (1:1). The fractions that show one spot of rf 0.85 on a fluorescent silica thin layer plate developed with benzene are combined. Evaporation of the solvent under reduced pressure leaves white crystals, m.p. 96.5°-97.5°C. A sample for analysis is sublimed.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][N:13]2[CH2:33][CH2:32][C:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15][CH2:14]2)=[C:4](Br)[CH:3]=1.[F:35][C:36]1[C:41]([F:42])=[C:40]([F:43])[CH:39]=[CH:38][C:37]=1B(O)O.O.[OH-].[Li+]>O1CCOCC1.O.C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:39]2[CH:38]=[CH:37][C:36]([F:35])=[C:41]([F:42])[C:40]=2[F:43])[C:5]([CH2:12][N:13]2[CH2:33][CH2:32][C:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15][CH2:14]2)=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(C(F)(F)F)c(C)cc4Br)CC3)OC2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2ccc(F)c(F)c2F)c(CN2CCC3(CC2)CN(c2ccc(C(=O)O)cc2)C(=O)O3)cc1C(F)(F)F
Temperature: 120 °C
Yield: 42.1 %

Procedure:
To a solution of methyl 4-{8-[(4-methyl-5-trifluoromethyl-2-bromophenyl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl}benzoate (30 mg, 0.055 mmol) in dioxane (1.5 mL) and water (0.5 mL) in a 5 mL microwave reaction vial were added 2,3,4-trifluorophenylboronic acid (20 mg, 0.111 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (9 mg, 0.011 mmol) and lithium hydroxide mono-hydrate (5 mg, 0.111 mmol). The reaction was heated in a microwave at 120° C. for 15-30 minutes. The crude reaction was diluted with acetonitrile and water, filtered and purified by reverse phase chromatography using a gradient of acetonitrile and water with 0.1% ammonium hydroxide. Lypholization of the desired fractions afforded the title compound (13.4 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](OC)([O:22]C)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].COCCOC.O.Cl>C(Cl)Cl>[CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(SC)c1cccc(C(OC)(OC)c2ccccc2)c1
Agent: Cl
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(SC)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.5 %

Procedure:
To 978 mg of methyl α-methylthio-α-[m-(α,α-dimethoxybenzyl)phenyl]propionate were added 2 ml of 1,2-dimethoxyethane and 0.5 ml of water, and 0.2 ml of conc. hydrochloric acid was further added. The mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with 50 ml of methylene chloride, and dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure to afford 874 mg of methyl α-methylthio-α-(m-benzoylphenyl)propionate. The product was found to be substantially pure by its NMR and GLC.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>O1CCOCC1>[C:38]([O:37][C:35]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:16]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:17]=[CH:18][N:19]=5)[S:8][C:7]=4[C:6]=3[N:28]=2)[CH2:31][CH2:30]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 112 °C
Yield: 54 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (208 mg×4, 2.0 mmol), tert-butyl piperazine-1-carboxylate (445 mg, 2.4 mmol), Pd(OAc) (45 mg, 0.20 mmol), Xphos (95 mg, 2.0 mmol), t-BuONa (460 mg, 4.0 mmol) and dioxane (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC (DCM/EtOAc=10:1) to give 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazine-1-carboxylic acid tert-butyl ester (612 mg, yield: 54%). 1HNMR (DMSO-d6, 400 MHz): δ8.30 (s, 1H), 7.99-7.90 (m, 1H), 7.79-7.70 (m, 2H), 7.32 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 4.19 (s, 4H), 4.04-4.02 (m, 4H), 3.44 (m, 1H), 3.12 (s, 1H), 1.57 (s, 9H) ESI-MS: m/z=567 [M+H+]
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=O.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].Cl>N1C=CC=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=[CH:18][C:19]([OH:21])=[O:20]
Reactant: O=Cc1cc(F)ccc1F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(F)ccc1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
Piperidine (2 mL, 20.2 mmol, 0.168 vol) was added to a stirred mixture of 2,5-difluorobenzaldehyde (12.07 g, 85.0 mmol, 1 wt) and malonic acid (18.28 g, 175.6 mmol, 1.51 wt) in pyridine (50 mL, 4.14 vol). The reaction mixture was heated under nitrogen and held at reflux (oil bath 100° C.) for 2 hours, effervescence was observed for about 90 minutes—initially vigorous then diminishing. The reaction mixture was then allowed to cool to 20 to 25° C. and poured into stirred 2 M hydrochloric acid (310 mL, 25.7 vol) (pH recorded as 1). The resulting precipitate was aged at 20 to 25° C. for 1 hour then filtered. The filter cake was washed with water (2×50 mL, 4.1 vol) then left to dry for a further 1 hour. The solid product was dried by dissolving it in TBME (250 mL, 20.7 vol), separating the phases and the water phase washed with TBME (100 mL, 8.3 vol). The TBME phases were combined, dried over magnesium sulphate (25 g, 2 wt), filtered and concentrated on a rotary evaporator to afford the product as a white solid (13.4 g, 85.7%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([NH2:14])[S:13][C:9]=2[CH:8]=1)[CH3:6])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([NH:14][S:19]([CH3:18])(=[O:21])=[O:20])[S:13][C:9]=2[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc2nc(N)sc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc2nc(NS(C)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4 (347 mg, 1 mmol) in pyridine (3 ml) is added to MsCl (0.13 ml, 1.21 mmol) at room temperature. The reaction mixture is stirred for 14 h at room temperature. 1N HCl (30 ml) is added to the mixture. The mixture extracted with ethyl acetate. The organic layer is dried over magnesium sulfate. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography(n-Hexane:EtOAc).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2].[Si]([O:29][C:30](=[CH2:36])/[CH:31]=[CH:32]/N(C)C)(C(C)(C)C)(C)C.C(Cl)(=O)C>CC(O)CC>[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:17][CH:32]=[CH:31][C:30](=[O:29])[CH2:36]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Reactant: C=C(/C=C/N(C)C)O[Si](C)(C)C(C)(C)C
Solvent: CC(=O)Cl
Solvent: CCC(C)O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 591.2 %

Procedure:
A suspension of 1-(4-isopropoxy-3-methoxy-benzoyl)piperidin-4-one (12.8 g, 44.0 mmol) in 2-butanol (100 mL) was purged with argon gas for 5 minutes. (1E)-3-[tert-butyl(dimethyl)silyl]oxy-N,N-dimethyl-buta-1,3-dien-1-amine (10.0 g, 4.0 mmol) was added dropwise at room temperature under argon gas. The reaction mixture was stirred at room temperature overnight. The mixture turned to a dark brown clear solution. Solvent was removed. The residue was redissolved in THF (200 mL) and cooled to −78° C. Acetyl chloride (3.75 mL, 52.8 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min. The reaction was quenched with saturated sodium bicarbonate (25 mL). The organic layer was separated. The aqueous layer was extracted with diethyl ether (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (8.5 g) as a light yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=6.1 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.94 (dd, J=8.2, 1.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 5.44 (d, J=6.1 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.25-4.00 (m, 2H), 3.87 (s, 3H), 3.34 (s, 2H), 2.56 (s, 2H), 2.15 (d, J=14.1 Hz, 2H), 1.62 (s, 2H), 1.39 (t, J=5.3 Hz, 6H). ESI-MS m/z calc. 359.17, found 360.3 (M+1)+; Retention time: 1.18 minutes (3 minute run).