Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:7][C:6]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[Cl:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a suspension of potassium carbonate (994 mg, 7.2 mmol) and 4-tert-butyl-3-chlorophenol (440 mg, 2.4 mmol) in acetone (5 ml) was added t-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 60° C. for 14 hours. Filtrating of potassium carbonate, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 10:1) to furnish the tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 100%). The mixture of tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 2.4 mmol), TFA (2.0 ml), DCM (2.0 ml) was stirred for 5 hours at room temperature. After being concentrated in vacuo, the residue was triturated with hexane to furnish the title compound (582 mg, 100%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 1.45 (9H, s), 4.67 (2H, s), 6.76 (1H, dd, J=2.6, 8.6 Hz), 6.96 (1H, d, J=2.6 Hz), 7.35 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH2:19].N1C=CC=CC=1.S(=[N:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Br:38])[C:32](Cl)=[O:33])=O>O1CCCC1>[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Br:38])[C:32]([NH:19][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:5][C:4]=1[CH3:18])=[O:33]
Reactant: O=S=Nc1cc(C(=O)Cl)ccc1Br
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(Br)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (0.31 g, 1.1 mmol) (prepared according to EP 1,006,102) in anhydrous tetrahydrofuran (2 ml), at 20° C., was added sequentially pyridine (0.174 g, 2.2 mmol) and a solution of 3-sulfinylamino-benzoyl chloride (0.25 g, 0.86 mmol) (Example 1.2) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred at ambient temperature for three hours. The reaction mixture was quenched by addition of water (5 ml). After separation of the phases, the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 3-amino-4-bromo-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.235 g, 78% yield). 1H-NMR (DMSO-d6, 400 MHz): 7.53 (d, 1H), 7.44 (s, 2H), 7.38 (d, 1H), 7.10 (q, 1H), 5.6 (s, 2H), 2.24 (s, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[C:31]([F:32])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:33])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:31]([F:32])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:33])[CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Yield: 40.7 %

Procedure:
To a mixture of 0.9503 g (3.0 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.6252 g (3.611 mmole) of 4-amino-2,5-difluorobenzoic acid, and 48 mL of dioxane, was added 1.96 g (6.01 mmole) of cesium carbonate and 0.0682 g (0.304 mmole) of palladium acetate. The mixture was deoxygenated with argon, 0.386 g (0.621 mmole) of 1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenyl phosphine was added and the reaction mixture was heated at 100 degrees for 3 hrs. The cooled mixture was concentrated under reduced pressure, dissolved in ethyl acetate, made slightly acidic by the addition of 1M hydrochloric acid, washed with water, brine, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.5533 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) as off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1F
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
Piperazine (6.0 g, 69 mmol) was dissolved in dimethylsulfoxide (50 ml), 2-fluorobenzonitrile (0.95 ml, 9 mmol) and potassium carbonate (2.2 g, 17 mmol) were added and the mixture was stirred at room temperature for 16 h. Water (100 ml) was added and the mixture was extracted with toluene (2×100 ml). The combined organic extracts were washed with 1 N sodium hydroxide (3×75 ml), dried (MgSO4) and concentrated in vacuo to give 1.48 g (88%) 2-(1-piperazinyl)benzonitrile as an oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C@@H:9]([CH:10]=[O:11])[CH2:8][C@H:7]2[CH2:12][C@@H:5]1[C:6]2([CH3:14])[CH3:13].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][N:3]=[C:4]1[C@@H:9]([CH2:10][OH:11])[CH2:8][C@H:7]2[CH2:12][C@@H:5]1[C:6]2([CH3:14])[CH3:13]
Reactant: CON=C1[C@@H](C=O)C[C@H]2C[C@@H]1C2(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CON=C1[C@@H](CO)C[C@H]2C[C@@H]1C2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,3S,5R)-2-(methoxyimino)-6,6-dimethylbicyclo[3.1.1]heptane-3-carbaldehyde, 77b, (0.70 g, 3.58 mmol) in methanol (15 mL) was added sodium borohydride (0.16 g, 4.30 mmol). After stirring at room temperature for 30 minutes, the reaction was diluted into aqueous saturated NaHCO3 solution and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-50% EtOAc/Hexanes gradient) to afford 330 mg of the desired alcohol as mixture of oxime isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:11])[CH:5]=1.[C:13](Cl)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[C:6]([I:11])[CH:5]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(I)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(C)=O)c(I)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-amino-3-iodo-benzoic acid methyl ester (11.1 g, 40.0 mmol) in anhydrous pyridine (80 mL) was added acetyl chloride (3.30 g, 42.0 mmol) at 0° C. under nitrogen. Stirring was continued at 0° C. for 30 minutes. The ice-bath was removed, and stirring continued at room temperature for 16 hours. Pyridine was evaporated under reduced pressure. The residue was taken in ethyl acetate (300 mL). The organic phase washed with 2 N aqueous HCl (200 mL), water (200 mL), brine (200 mL), and was dried over anhydrous Na2SO4. Removal of solvent gave 4-acetylamino-3-iodo-benzoic acid methyl ester as a white solid. Yield: 12.7 g (99%).
Reaction SMILES: Br[C@@H:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH3:3].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[F:15][C:14]([F:17])([F:16])[C:6]1[CH:5]=[C:4]([CH:2]([N:18]=[N+:19]=[N-:20])[CH3:3])[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -16.5 °C
Reaction time: 4 h
Yield: 117.2 %

Procedure:
A solution of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) (106 mg, 0.336 mmol, 99% ee) obtained in 1-(a) mentioned above in N,N-dimethylformamide (1 mL) was added with sodium azide (64.4 mg, 0.990 mmol), and the mixture was stirred at −18 to −15° C. for 4 hours. The reaction solution was extracted with ethyl acetate/n-hexane (1:1) and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 111.5 mg of 1-[3,5-bis(trifluoromethyl)phenyl]ethyl azide (crude product: 111.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][N:25]=[CH:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCCn1ccnc1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCn1ccnc1

Procedure:
Compound IIc was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(1H-imidazol-1-yl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=[O:9])[CH2:4][C:5]([O:7]C)=O.[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:10][C:2]([CH3:1])([CH3:11])[C:3](=[O:9])[CH2:4][C:5]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=1[Cl:12])=[O:7]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: Nc1ccc(Cl)cc1Cl
Product: CC(C)(C)C(=O)CC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 83.9 %

Procedure:
Methyl 4,4-dimethyl-3-oxopentanoate (100 g, 0.632 mol) and 2,4-dichloroaniline (100 g, 0,617 mol) were heated at reflux for 6 hours in xylenes (reagent grade, dried over 4A molecular sieves, 150 mL) in a flask equipped with mechanical stirrer and distillation apparatus. 100 mL of distillate was collected during this period. The reaction mixture was then cooled to room temperature and petroleum ether (500 mL) was added with stirring. The mixture was cooled further with an ice bath, and the crystals which had formed were collected by filtration and washed with petroleum ether. A second crop was collected after concentration of the filtrate. The combined materials were dried under high vacuum to give N-[4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (152.8 g, 84% yield) as a white solid which melted at 77°-78° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[O:4][N:3]=1.Cl.C(O)C.CC(OC)(C)C>ClCCl>[CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[O:4][N:3]=1
Reactant: Cc1noc(C2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1noc(C2CCCNC2)n1
Temperature: 40 °C
Yield: 114.4 %

Procedure:
tert-Butyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 2a,b (0.81 g, 0.0030 mol) was dissolved in 5 mL dichloromethane. Hydrochloric acid in ethanol (2.5 M) (2.43 mL, 0.0060 mol) was added and the mixture was heated to 40° C. for 3 hours. 20 mL of MTBE was added and the product precipitated from solution. The solids were filtered and washed with 3×5 mL MTBE and dried under vacuum overnight to obtain 574 mg of a white solid in 94% yield. MS (ESI) m/z 168 [M+1]+. 1H NMR (DMSO-d6) δ 1.74-1.82 (m, 3H), 2.11-2.14 (d, 1H), 2.31 (s, 3H), 2.87 (t, 1H), 3.10-3.30 (m, 2H), 3.49-3.56 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[CH:8]3[O:10][CH:9]3[C:4]=2[CH:3]=1.[OH-].[Na+].C(O)C.Cl[O-].[Na+]>O>[CH3:11][C:7]1([CH3:12])[O:6][C:5]2=[CH:13][C:14]3[C:2]([CH:3]=[C:4]2[CH:9]2[O:10][CH:8]12)=[N:1][O:16][N+:15]=3[O-:17]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C2OC21
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2cc3c(cc2C2OC21)no[n+]3[O-]

Procedure:
To a mixture of 4.41 g (18.9 m mol) of 6-amino-3,4-dihydro-2,2-dimethyl-3,4-epoxy-7-nitro-2H-benzo [b] pyran, 1.29 g (32 m mol) of sodium hydroxide, 400 ml of ethanol and 40 ml of water were added slowly dropwise 32.2 g (26 m mol) of 6% sodium hypochlorite solution at the room temperature with stirring.
Reaction SMILES: Cl[C:2]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=[C:13]([C:14]([O:16]C)=[O:15])[C:8]=2[N:7]=[C:6]1[CH:24]([F:26])[F:25].[Li+].[OH-].[CH2:34]1COCC1>>[Cl:31][C:30]1[C:2]([CH3:34])=[C:3]([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=3[N:7]=[C:6]2[CH:24]([F:26])[F:25])[CH:27]=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [OH-]
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 45 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of methyl 1-(2,3-dichlorobenzyl)-2-(difluoromethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate (1045 mg, 2.3 mmol) in THF (40 mL) was added into 2 N LiOH (20 mL) and the mixture was stirred at 45° C. for 4 h. It was filtered, the filter cake was added to water (100 mL) and formic acid was added to adjust pH=3. Then a filtration was performed, the filter cake was collected and washed with water (200 mL), dried under vacuum to give the desired product (800 mg, 80%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.46 (s, 3H), 3.13 (t, 4H, J=4.8 Hz), 3.73 (t, 4H, J=4.8 Hz), 3.92 (s, 3H), 5.70 (s, 2H), 6.00 (d, 1H, J=7.5 Hz), 7.04 (t, 1H, J=7.5 Hz), 7.23 (d, 1H, J=1.8 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.36 (t, 1H, J=51.9 Hz), 7.57 (d, 1H, J=1.8 Hz), 12.96 (br s, 1H); LC-MS: m/e=436 [M+1]+
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:6]([C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:6]([C:10]1[CH:15]=[C:14]([S:16][CH:3]([CH3:4])[CH2:2][CH:1]=[O:5])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C/C=C/C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(CC=O)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
3.12 Grams of crotonaldehyde(0.042 mole) are added dropwise over a 15 minute period at 17°-22° C. to a solution of 10.8 grams of 2,6-di-tert-butyl-4-mercaptophenol (0.044 moles) and 0.5 gram of triethylamine in 20 ml of toluene and allowed to react in a nitrogen atmosphere at room temperature for 30 minutes and then at 50°-55° C. for two hours. Analysis indicates that the reaction is substantially complete at this point. The product, isolated as a light yellow liquid, is obtained in nearly quantitative yield after stripping off volatiles at 40° to 50° C. at 0.15 mm. Hg.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (200 mg, crude) in dioxane (6 mL) was added benzofuran-2-ylboronic acid (113.0 mg, 0.70 mmol), K3PO4 (220.0 mg, 1.04 mmol), Pd(PPh3)4 (20.1 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford (S)-methyl 2-(benzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a red oil (100.0 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12](Cl)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:13])[CH2:11][CH2:10]2
Reactant: COc1ccc(CCC(=O)Cl)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1Br)CCC2=O
Reaction time: 2 h

Procedure:
48 g (0.18 mol) of 3-(3-bromo-4-methoxyphenyl)propanoyl chloride are dissolved in 500 ml of dichloromethane. 72 g (0.54 mol) of aluminium chloride are added in small amounts. The reaction medium is stirred for 2 hours and then poured into water and the phases are separated by settling. The organic phase is dried (Na2SO4) and the solvent is evaporated off: (39.8 g). The product is triturated in ethanol, filtered off and dried (25 g; 63%)
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH3:17]>C1(C)C=CC=CC=1.CN(C=O)C.Cl>[C:5]1([C:11]2([C:14]([NH2:17])=[O:16])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)C1(c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Thionyl chloride (0.225 mL, 3.08 mmol) was slowly added to a solution of 1-phenylcyclopropanecarboxylic acid (0.50 g, 3.08 mmol) in toluene (10 mL) and DMF (0.3 mL). The reaction was then heated at reflux for 2 hours, then cooled down to 23° C. and treated (slow addition) with a solution of ammonia (2M in methanol, 10 mL). The reaction was then stirred at 23° C. overnight. The reaction was then diluted with hydrochloric acid (1N) and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude title material (0.474 g, 95%) as a solid which was used as such in the next reaction. 1H NMR (400 MHz, CDCl3) δ: 1.11 (2H, q, J=3.79 Hz), 1.60-1.66 (2H, m), 5.34 (1H, br s), 5.91 (1H, br s), 7.31-7.41 (3H, m), 7.43-7.47 (2H, m). HPLC ret. time (Condition B): 1.225 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1.N1C=CC=CC=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1)([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)n1c(OCCCCCO)nc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)n1c(OCCCCCOS(=O)(=O)c2ccc(C)cc2)nc2ccccc21
Reaction time: 5 h
Yield: 69.1 %

Procedure:
A solution of 2 g of the compound obtained in Example 14a in 20 ml of dichloromethane was added with 5 ml of pyridine and 1.8 g of p-toluenesulfonyl chloride and stirred for 5 hours. The organic layer was washed with 10% aqueous citric acid and then with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 2.2 g of the title compound (yield: 69%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH2:26])=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=O)[CH:32]=[N:33][CH:34]=1.C([BH3-])#N.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:35][C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Reactant: O=Cc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(Cc2sc(NCc3cncc(F)c3)nc2Cl)c2cc(Cl)cnc21
Yield: 49.7 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine (592, 50.0 mg, 0.11 mmol, prepared as described in Example 66, Scheme 183) in ethanol (1.60 mL) and acetic acid (0.08 mL) were added 5-fluoro-pyridine-3-carbaldehyde (594, 43 mg, 0.34 mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.180 g). The reaction was irradiated with microwave on 300 watts, 100° C. for 7 minutes. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound (595, 0.030 g, 48%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[N:4]=[C:3]1[CH3:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:52]([O:54][C:55](=[O:76])[C@H:56]([O:58][C:59]1[CH:64]=[C:63](Cl)[N:62]=[C:61]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:60]=1)[CH3:57])[CH3:53]>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].O1CCOCC1>[F:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:61]1[N:60]=[C:59]([O:58][C@@H:56]([CH3:57])[C:55]([O:54][CH2:52][CH3:53])=[O:76])[CH:64]=[C:63]([NH:10][S:7]([C:5]2[N:4]=[C:3]([CH3:11])[N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[N:62]=1
Reactant: Cc1nc(S(N)(=O)=O)cn1C
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](C)Oc1cc(NS(=O)(=O)c2cn(C)c(C)n2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 1,2-Dimethyl-1H-imidazole-4-sulfonic acid amide (0.19 g), tris(dibenzylideneacetone)dipalladium (0) (56 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (41 mg), cesium carbonate (0.32 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 11 step i) (0.24 g) and dioxane (20 mL). Purification was by column chromatography on silica gel using DCM/MeOH (100:1 to 90:10 gradient) as eluent, to give the title compound as a pale yellow solid. Yield: 0.25 g