Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.C(Cl)(=O)OCC.[C:14]([O:18][C:19](=[O:32])[C@@H:20]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[CH2:21][C:22](O)=[O:23])([CH3:17])([CH3:16])[CH3:15].C(O)(=O)CCC=C.[CH3:40][S-:41].[Na+]>C1COCC1.CN(C=O)C.ClCCl.O>[CH3:40][S:41][C:22](=[O:23])[CH2:21][C@H:20]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:32]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: C[S-]
Agent: C=CCCC(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 85 %

Procedure:
Et3N (1.54 ml, 11.0 mmol) and ethyl carbonochloridate (1.05 ml, 11.0 mmol) were added to a solution of the mixed crude product A (1.96 g, 9.68 mmol) of (S)-4-(tert-butoxy)-4-oxo-3-(pent-4-enamido)butanoic acid (Compound 1b-I) and pent-4-enoic acid (1:0.8) in THF (44 ml), and the mixture was stirred at room temperature for 25 minutes. A solution of sodium methanethiolate (1.06 g, 15.1 mmol) in DMF (18 ml) was then added to the reaction mixture, which was stirred at room temperature for 1 hour. Water was then added to the reaction mixture, followed by dilution with dichloromethane. The organic layer was washed with water, and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→40/60) to afford (S)-tert-butyl 4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1e-IA) (1.38 g, 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:7]=1.CC1(C)C(C)(C)OB([C:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=2)O1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)[CH:3]=[CH:4][C:5]=1[CH3:14])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(Br)cc1NC(=O)C(C)C
Product: Cc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)C(C)C

Procedure:
Prepared by Procedure W and Scheme AF using N-(5-bromo-2-methylphenyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 259.1 (M - 100)+.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1C=[CH:17][NH:18]2>ClC(Cl)C>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:7]([CH:6]=[O:10])=[CH:17][NH:18]2
Reactant: COc1cccc2[nH]ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccc2[nH]cc(C=O)c12
Yield: 96.3 %

Procedure:
A solution of dry DMF (0.75 g) in 50 ml dichloroethane was cooled to 0° C. and placed under nitrogen. Oxalyl chloride (1.03 g) dissolved in dichloroethane (5 ml) was added dropwise with stirring. The solution was stirred until no more bubbling was observed (about 15-20 m). 4-Methoxyindole (1.0 g, 6.7 mmole) was added to the solution as a solid and the reaction mixture was stirred at room temperature for four hours. The reaction was quenched by careful addition of 10% sodium carbonate solution. The two phase mixture was stirred at room temperature for 2 hours. The layers were separated and the aqueous layer was extracted with methylene chloride, and the combined organic extracts were dried and evaporated to dryness. The crude residue was passed through a short silica gel column, eluting with 3:7 ethyl acetate:hexane to 1:1 ethyl acetate:hexane to yield 1.13 g (95%) of 4-methoxy-1H-indole-3-carbaldehyde.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:39])[CH2:33][CH:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)[CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:40])[N:17]=2)[CH2:12][CH2:11]1>>[NH2:40][C:18]1[N:19]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:39])[CH2:33][CH:34]4[CH2:38][CH2:37][N:36]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:35]4)[CH2:29]3)=[CH:24][CH:23]=2)[CH:21]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]2)[N:17]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C)OC(=O)N1CCC(CC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 118, Step 3 starting from isopropyl chloroformate and 4-(4-methylpiperazin-1-yl)-6-[2-(pyrrolidin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=522.2.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[N:17][N:18]=2)[N:4]=1
Reactant: NNC=O
Reactant: Fc1ccccc1-c1ccc(Cl)nn1
Solvent: CCCCO
Product: Fc1ccccc1-c1ccc2nncn2n1

Procedure:
A mixture of 5.0 g. of 3-chloro-6-(o-fluorophenyl)pyridazine and 2.88 g. of formylhydrazine in 75 ml. n-butanol is refluxed for 48 hrs. and worked up as in Example 35 to give 1.1 g. of product as cream colored crystals, m.p. 161°-163° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[C:36]([C:37]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: Anal. Calcd for C30H35ClFN3O4+CH2Cl2: C, 63.3; H, 6.23; N, 7.33. Found: C, 63.0; H, 6.39; N, 7.03; ESMS m/e: 556.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].Br[CH:11]([CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:13]>C1COCC1>[CH3:9][O:8][C:6](=[O:7])[CH:5]([C:3]#[N:4])[CH:11]([CH3:24])[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23]
Reactant: CC(Br)C(=O)c1ccccc1C(F)(F)F
Reactant: COC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(C)C(=O)c1ccccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a suspension of NaH (60%, 2.88 g, 72 mmol) in anhyd THF (200 mL) was added methyl cyanoacetate (4.5 mL, 50 mmol). After this mixture was stirred for 3 h at 20° C., a solution of 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one (13.5 g, 48 mmol) was added and the mixture was stirred overnight at 20° C. The mixture was quenched with water and the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (13.3 g, 93%), which was used in the next step without purification. MS (ES): 300 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[H-].[Na+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1)[CH3:28]
Reactant: CCOC(=O)CCBr
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A suspension of 4.00 g (12.77 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and 1.63 ml (12.77 mmol) of ethyl 3-bromopropionate in 60 ml of DMF was treated at 0° C. with 0.61 g (14.05 mmol) of NaH (55% in oil) in two portions. The suspension was stirred after 30 min at RT to get a solution and further stirred over night at 0° C. The reaction was neutralized with cold aqueous 10% KHSO4 and extracted with EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and crystallized (dichloromethane/MeOH) to yield 3.71 g (70%) of the titled compound as an off-white solid. MS: 413.1 (MH+, 2Cl).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][N:5]([CH3:9])[CH2:6][CH2:7][OH:8].[H-].[Na+].[C:13]([NH2:17])(=[O:16])[CH:14]=[CH2:15].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][N:5]([CH3:9])[CH2:6][CH2:7][O:8][CH2:15][CH2:14][C:13]([NH2:17])=[O:16]
Reactant: CN(C)CCN(C)CCO
Reactant: C=CC(N)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(C)CCOCCC(N)=O
Temperature: 25 °C

Procedure:
A 50 ml 3 neck round bottom flask was fitted with the following: magnetic stirrer, reflux condenser, air bubbler, and a temperature controlled oil bath. The flask was charged with 7.3 g of 2-{[2-(dimethylamino)ethyl]methylamino}ethanol. Sodium hydride, 0.014 g, was then added carefully to the of 2-{[2-(dimethylamino)ethyl]methylamino}ethanol with stirring. The mixture was stirred at a constant rate for two minutes before 3.55 g of acrylamide was added. After the addition of acrylamide, the reaction mixture was stirred at 50° C. for 6 hours. The mixture was cooled to ambient temperature. Concentrated sulfuric acid, 0.034 g, then was added to neutralize the product mixture. The resulting mixture was filtered through a Celite layer. The filtrate was collected for foam application. Quantitative 1H NMR showed that the product was 94% pure.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O-:13])(=[O:12])[CH2:10][CH3:11].[K+]>C(O)(=O)CC.[Mn+3]>[CH3:11][CH:10]1[CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:13][C:9]1=[O:12]
Reactant: CCC(=O)[O-]
Reactant: C=Cc1ccccc1
Agent: [Mn+3]
Agent: [K+]
Solvent: CCC(=O)O
Product: CC1CC(c2ccccc2)OC1=O
Yield: 50 %

Procedure:
Styrene in an amount of 2.1 grams and 11.65 grams of manganic acetate, Mn(C2H3O2)3.2H2O, comprising two equivalents of Mn+3 based on titration value, were refluxed under nitrogen in 200 milliliters of propionic acid containing 20 grams of potassium propionate. In less than an hour, a 50% yield of alpha-methyl-gamma-phenyl butyrolactone was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C:12]1([CH2:18][C:19](O)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][C:12]1([CH2:18][CH2:19][OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(CC(=O)OCc2ccccc2)CCCCC1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC1(CCO)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of (1-benzyloxycarbonylmethyl-cyclohexyl)-acetic acid (3.0 g, 10 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C. and 1 M borane-THF complex in tetrahydrofuran (21 mL, 20 mmol) was added dropwise over 5 min. The reaction mixture was allowed to warm to room temperature, stirred for 1 h at room temperature. and cooled to 0° C. Methanol was added slowly to quench the reaction. The reaction mixture was warmed to room temperature, stirred for 30 min, and concentrated to dryness to provide the title compound (2.2 g).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2([C:41]([F:44])([F:43])[F:42])[O:32][N:31]=[C:30]([C:33]3[S:34][C:35]([C:39]#[CH:40])=[C:36]([CH3:38])[CH:37]=3)[CH2:29]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1>CN(C=O)C.[Cu]I>[CH2:1]([N:8]1[CH:40]=[C:39]([C:35]2[S:34][C:33]([C:30]3[CH2:29][C:28]([C:23]4[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=4)([C:41]([F:44])([F:43])[F:42])[O:32][N:31]=3)=[CH:37][C:36]=2[CH3:38])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1-c1cn(Cc2ccccc2)nn1
Reaction time: 16 h
Yield: 25.6 %

Procedure:
CuI (47 mg) is added to a solution of benzylazide (33 mg), DIPEA (1.05 ml) and 5-(3,5-dichloro-phenyl)-3-(5-ethynyl-4-methyl-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole (100 mg) in DMF (2.0 ml). After 16 hours at room temperature, the reaction is quenched with a saturated aqueous solution of NaHCO3 and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 1-benzyl-4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-1H-[1,2,3]triazole (34 mg) as a yellowish foam. MS (HPLC/MS): 537 (MH+). Retention time: 5.04 min.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:16]([CH2:19][C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:21]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:11]1([S:16]([CH2:19][C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH:37][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:35][CH:34]=3)[N:21]=2)(=[O:17])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Phenyl chloroformate (0.759 mL, 6.05 mmol) was added to 4-[4-(cyclopentylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.68 g, 4.03 mmol) and sodium hydrogen carbonate (0.508 g, 6.05 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (2.10 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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:8][C:5]1[CH:4]=[CH:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OB(O)c1ccccc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (2.33 g, 13.2 mmol) in toluene (100 mL) and ethanol (25 mL) were added Pd(PPh3)4 (764 mg, 0.66 mmol), phenylboronic acid (2.42 g, 19.8 mmol, 1.5 eq) and a solution of sodium carbonate (9.6 g, 90.7 mmol, 6.85 eq) in water (50 mL). The reaction mixture was heated to 90 C for 2 hours, allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was dried and evaporated and the residue purified by column chromatography (petrol/ethyl acetate gradient) to afford the title compound as a colorless oil (2.14 g, 93%)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[C:12]([CH2:14][C:15]([NH2:17])=[S:16])#[N:13]>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:15]([CH2:14][C:12]#[N:13])[S:16][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: N#CCC(N)=S
Product: N#CCc1nc(-c2ccc(Br)cc2)cs1
Yield: 48 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-bromophenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (2.4 g, 48% yield), and it was carried through without further purification. MS (ESI) m/z: Calculated for C11H7BrN2S: 277.95. found: 279.0 (M+H)+.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:19])=[CH:10][C:11](=[O:18])[N:12]3[CH2:15][CH:16]=O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][N:31]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[CH:1]1([O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:19])=[CH:10][C:11](=[O:18])[N:12]3[CH2:15][CH2:16][N:42]3[CH2:43][CH2:44][CH:39]([N:31]([CH2:30][C:28]4[CH:27]=[CH:26][C:25]5[O:20][CH2:21][CH2:22][O:23][C:24]=5[CH:29]=4)[C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:40][CH2:41]3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(CC=O)c2cc(OC3CC3)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC3CC3)ccc12
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
To 2 mL of dichloromethane solution containing 60 mg of (7-cyclopropoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde, 81 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 20 μL of acetic acid were added, and stirred for 15 min. To the reaction mixture, 74 mg of sodium triacetoxyborohydride was added, and stirred for 40 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:4], to give 0.10 g of tert-butyl (1-(2-(7-cyclopropoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[N:19]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[N:19]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: FC(F)(F)c1ccc(Nc2ncnc(/C=C/c3ccc4c(cnn4C4CCCCO4)c3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Nc2ncnc(CCc3ccc4c(cnn4C4CCCCO4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of (E)-4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (0.03 g, 0.064 mmol) in ethyl acetate (3 mL), Pd—C (0.014 g, 0.129 mmol) was added and the reaction mixture was stirred at room temperature under H2 overnight. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate, and concentrated to get 4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine as a yellow gum (0.03 g, 75% yield). LCMS: R.T.=1.06 min; [M+H]+=469.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[Br-].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Zn+])=[CH:26][CH:25]=1)#[N:23]>O1CCCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: N#Cc1ccc([Zn+])cc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Agent: Cl[Pd]Cl
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound of Example 2 (6.5 g, 17 mmol) and bis(triphenylphosphine) palladium dichloride (0.15 g, 0.45 mmol) were dissolved in tetrahydrofuran (60 mL). The compound 4-cyanophenylzinc bromide (Rieke Organometallics, Lincoln, Nebr., 0.28M in tetrahydrofuran, 72 ml) was added over 2 min and the mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with water (200 mL) and extracted with ether (100 mL). The aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layers were dried over magnesium sulfate and evaporated. The residue was subjected to silica gel chromatography with hexanes/ethyl acetate 5:1 as eluent. The title compound was isolated as a yellow solid (4.5 g): m.p. 136°-138° C. 1H NMR (CDCl3, 300 MHz) δ 7.8-7.0 (11H), 5.6 (1H), 4.9 (1H), 4.3 (1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=4[Cl:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Yield: 76.7 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-dichlorophenylboronic acid (3.73 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (75%) of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C22H18Cl2O4S: C, 58.8; H, 4.04. Found: C, 59.01; H, 4.09.