Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[Cl:27]>>[Cl:27][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:19]=1[CH2:18][NH:17][C:12](=[O:14])[CH:11]([C:3]1[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[O:15][CH3:16]
Reactant: N#Cc1ccc(CN)c(Cl)c1
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2Cl)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid, described in example 66.1 was coupled with 4-aminomethyl-3-chlorobenzonitrile (CAS 202521-97-9) according to general procedure C to give (RS)-N-(2-chloro-4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Light yellow oil. MS 379.2 ([M−H]−)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15])[CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:24][C:25]1[N:29]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])[N:28]=[CH:27][C:26]=1[CH:38]([CH3:40])[CH3:39].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]2[N:29]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:37])[N:28]=[CH:27][C:26]=2[CH:38]([CH3:40])[CH3:39])=[CH:10][C:9]=1[CH3:15])[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)c1ccc(O)cc1C
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of (+/−)-3-(4-Hydroxy-2-methyl-phenyl)-butyric acid ethyl ester (0.366 g, 0.748 mmol) in DMF (4 mL) is added cesium carbonate (1.1 g, 1.5 mmol). After 5 minutes at room temperature, 5-Chloromethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (0.50 g, 0.748 mmol) is added and the reaction is heated to 50° C. overnight. Upon cooling, water is added followed by 1N HCl. The resulting mixture is extracted two times with ethyl acetate and the organic layers are combined and are washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with 3-5% ethyl acetate/toluene to give the title compound. 1H NMR (CDCl3) δ 1.113-1.163 (m, 6H), 1.26 (d, 6H), 2.399-2.532 (m, 2H), 2.952 (m, 1H), 3.388 (m, 1H), 4.024 (q, 2H), 4.741 (s, 2H), 6.513 (d, 1H), 6.544 (dd, 1H), 6.970 (d, 1H), 7.264 (t, 1H), 7.372 (d, 2H), 7.661 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15]COCC>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: CCOCC
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Product: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (3.00 g, 11.2 mmol) in Et2O (50 mL) was added a solution of CH2N2 in Et2O (2M, 50 mL, 100 mmol) at rt and the mixture was stirred for 10 min, concentrated and purified by CC (PE/EA=10/1) to give compound P42a (2.51 g, 80%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[C:15]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:16])[CH3:11]
Reactant: CC#CC(=O)OCC
Reactant: COc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C=C(C)Oc1ccc(OC)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 4-methoxy-phenol (1.10 g, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 10-20% ethyl acetate/hexanes) afforded 3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (0.99 g, 47%) as a clear oil: HR-ES-MS m/z calculated for C13H16O4 [M+H]+ 237.1122, observed 237.1121; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.0 Hz, 3H), 2.41 (s, 3H), 3.76 (s, 3H), 3.98 (q, J=7.0 Hz, 2H), 4.63 (s, 1H), 6.99 (d, J=9.1 Hz, 2H), 7.05 (d, J=9.1 Hz, 2H).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1.[CH3:17][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:15])[CH3:17])=[CH:10][CH:9]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
N-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (19.1 g, 81.6 mmol) was dissolved in tetrahydrofuran (410 mL). The system was purged with N2 and then cooled to 0° C. 1.4 M of methylmagnesium bromide in toluene/THF (75:25) (87.4 mL, 122.4 mmol) was added dropwise using an additional funnel. At the end of the addition the mixture was cloudy off-white. The mixture was stirred at 0° C. for 1 hour and carefully quenched by dropwise addition of 1 M aq. HCl (150 mL) and diluted with ethyl ether (300 mL) and EtOAc (100 mL). The organic layer was separated and washed with 0.1 M aq. NaOH (200 mL) and brine (2×50 mL), dried (Na2SO4), and concentrated to yield a light yellow solid (15.04 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)cc1Cl
Yield: 38.6 %

Procedure:
Using 0.10 g of 2-chloro-4-(trifluoromethyl)benzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and. 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.05 g of 2-(2-chloro-4-(trifluoromethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (41)).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][OH:38])[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(dimethyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M284) (0.46 g, 0.70 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].S(O[CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOCCC1(CCOCCOCCOC)c2cc(Br)ccc2-c2ccc(Br)cc21
Yield: 60 %

Procedure:
2,7-dibromofluorene (5.0 g, 15.4 mmol) was dissolved in dried THF solution (30 mL). Sodium hydride (1.0 g, 40 mmol) was added to the THF solution at room temperature and refluxed for 5 hours. 1-Tosyloxy-3,6,9-trioxadecane (11.8 g, 37 mmol) in 20 mL of dry THF was added drop-wise to the refluxed solution. The mixture was allowed to refluxed over night, then cooled down, poured into distill water and extracted with chloroform (2×100 mL). The combined organic solutions were washed with saturated NaCI solution (2×100 mL), distilled water (1×100 mL), dried over MgSO4, and concentrated under reduced pressure. Crude oil was further purified by column chromatography using hexane/ethyl acetate (50/50) as eluant. TLC (ethyl acetate/Hexane=1/1) Rf =0.12. The fraction at Rf=0.12 was collected and concentrated to give 5.7 product in 60% yield. 1H NMR (300 MHz, CDCl3), 2.34(t, 4H), 2.77(t, 4H), 3.10-3.60(m, 22H), 7.40-7.60(m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:20]([O-])=O.C(O)C.[H][H]>[Pd]>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCOCC1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reaction time: 8 h
Yield: 97.4 %

Procedure:
4-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine (0.24 g, 0.00078 mol) was dissolved in ethanol (40 mL, 0.7 mol) and placed in a Parr bottle. To this solution was added palladium on carbon (10 mg). The reaction mixture was placed under 50 psi of hydrogen and shaken overnight. The mixture was filtered through celite and washed with additional ethanol (40 mL). The filtrate was concentrated in vacuo. The film was triturated with diethyl ether to provide 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine as a solid (0.21 g, 97%). 1H NMR (400 MHz, CDCl3) δ 6.71 (d, 1H, J=7.84 Hz), 6.51 (d, 1H, J=7.83 Hz), 3.70 (s, 7H), 3.31 (m, 1H), 2.75 (m, 1H), 2.60 (m, 2H), 2.55 (s, 4H), 2.31 (m, 1H), 2.0-2.16 (m, 2H), 1.37 (m, 2H).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[CH3:37])=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OCC[C@H]2CCCCN2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC[C@H]2CCCCN2C)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 12 h
Yield: 68.1 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-((R)-2-piperidin-2-yl-ethoxy)-pyridazine dihydrochloride (0.065 mmol, 0.033 g) and aqueous formaldehyde (37%, 0.323 mmol, 0.03 mL) in dry DCM (2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.39 mmol, 0.165 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (5 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-[2-((R)-1-methyl-piperidin-2-yl)-ethoxy]-pyridazine (0.02 g, 73%). The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.025 g). LCMS: m/z 453 [M+1]. 1H NMR (400 MHz, CD3OD) δ 6.97-7.45 (5H, m), 4.55-4.72 (2H, m), 4.35-4.46 (1H, m), 3.46-3.82 (1H, m), 3.05-3.19 (1H, m), 2.79-3.06 (5H, m), 2.44-2.74 (2H, m), 2.10-2.36 (2H, m), 1.74-2.06 (9H, m), 0.79 (3H, t).
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:3].[NH2:20]CC(O)=O>C(OCC)(=O)C>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:4]([C:2]([NH2:20])=[O:3])=[CH:5][C:6]1=2
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: NCC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Reflux 1.0 gm of 2-chlorocarbonyl-6,11-dihydro-11-oxodibenz[b,e]oxepin in 20 cc of ethyl acetate containing 2.0 gm of glycine for 5 hours. Evaporate the mixture to dryness. Add 30 cc of water to the solid residue and stir at room temperature for one hour. Separate the solid by filtration and recrystallize from ethanol to obtain the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:32]([O:34]CC)=[O:33])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:32]([OH:34])=[O:33])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CCC(C(=O)O)(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate (200 mg, 0.37 mmol) and lithium hydroxide monohydrate (88 mg, 3.7 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylic acid in 67% yield (150 mg). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.88 (m, 2H); 1.41 (m, 4H), 0.98 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[Mg]Br)[CH3:4].BrC1C(CC)=CC(C)=CC=1CC.[Mg]>C1COCC1>[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[CH2:1][OH:2])[CH3:4]
Reactant: CCc1cc(C)cc(CC)c1[Mg]Br
Reactant: C=O
Agent: CCc1cc(C)cc(CC)c1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Over a period of 30 min, gaseous formaldehyde (generated from 5.56 g of paraformaldehyde) is introduced with stirring into a solution of 2,6-diethyl-4-methylphenylmagnesium bromide, prepared from 12.40 g (54.6 mmol) of 1-bromo-2,6-diethyl-4-methylbenzene and 1.47 g (60.65 mmol) of magnesium turnings in 50 ml of THF, and the mixture is then stirred at room temperature for another 2 h. Distillative removal of the solvent and chromatography on silica gel (see above) gives 6.88 g (71%) of 2,6-diethyl-4-methylbenzyl alcohol.
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu-]=O>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: c1cn[nH]c1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CCc2c(ccc(-n3cccn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.2 %

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1 (2H)-yl)(cyclopropyl)methanone (0.300 g, 0.78 mmol), 1H-pyrazole (0.053 g, 0.78 mmol), copper (I) oxide (0.056 g, 0.39 mmol), cesium carbonate (0.508 g, 1.56 mmol) in N,N-dimethylformamide (5 mL) stirred for 18 h at 100° C. The resulting mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:10, ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1 (2H)-yl)methanone (0.050 g, 17%) as a yellow solid. MS (ESI, pos. ion) m/z 374 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH2:15])[CH:11]=[CH:12]2)=[N:7]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:15][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:26][CH:27]=3)=[O:33])[CH:11]=[CH:12]2)=[N:7]1
Reactant: COC(CCn1cc2ccc(N)cc2n1)OC
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(CCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1)OC

Procedure:
To a stirred solution of 2-(3,3-dimethoxypropyl)-2H-indazole-6-ylamine (582 mg, 2.48 mmol) in THF (9 mL) was added 4-phenoxyphenylisocyanate (523 mg, 2.48 mmol) and the reaction was heated to 40 C for 3 h. The heating bath was removed and the reaction was then concentrated under reduced pressure to a dark oil. The oil was dissolved in Ethyl acetate and passed through a small plug of SiO2 gel, eluting with additional EtOAc. The eluent was concentrated under reduced pressure to give 1-[2-(3,3-dimethoxypropyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea as a beige solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.50 (m, 2 H), 3.32 (m, 6 H), 4.36 (m, 3 H), 6.97 (m, 6 H), 7.09 (t, J=7.46 Hz, 1 H), 7.36 (m, 2 H), 7.48 (m, 2 H), 7.59 (d, J=8.82 Hz, 1 H), 7.83 (s, 1 H) and 8.66 (m, 2 H); MS(ESI) 445 (M−H)−.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:34]1([C@@H:39]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[C:40]([OH:42])=O)[CH2:38][CH2:37][CH2:36][CH2:35]1.[NH2:50][C:51]1[CH:52]=[C:53]([CH:65]=[CH:66][CH:67]=1)[CH2:54][C:55]1([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:57][CH2:56]1>CN(C=O)C>[CH:34]1([C@@H:39]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[C:40]([NH:50][C:51]2[CH:52]=[C:53]([CH:65]=[CH:66][CH:67]=2)[CH2:54][C:55]2([C:58]([O:60][C:61]([CH3:64])([CH3:62])[CH3:63])=[O:59])[CH2:57][CH2:56]2)=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Reactant: Cc1ccc([C@@H](C(=O)O)C2CCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([C@@H](C(=O)Nc2cccc(CC3(C(=O)OC(C)(C)C)CC3)c2)C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
At RT, 453 mg (1191 μmol) of HATU and 479 μl (2750 μmol) of N,N-diisopropylethylamine were added to a solution of 200 mg (916 μmol) of (+)-(2S)-cyclopentyl(4-methylphenyl)acetic acid in 1 ml of DMF. The mixture was stirred for 30 min. 249 mg (1008 μmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were then added. The reaction mixture was stirred overnight and then directly separated into its components by preparative HPLC. This gave 328 mg (80% of theory) of the title compound.
Reaction SMILES: [CH:1](=[N:8][S:9][C:10]1[C:11]([Cl:16])=[N:12][CH:13]=[CH:14][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:18].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH:1](=[N:8][S:9]([C:10]1[C:11]([Cl:16])=[N:12][CH:13]=[CH:14][N:15]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccnc1SN=Cc1ccccc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(N=Cc1ccccc1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1.25 grams (0.005 mole) of N-benzylidene-2-chloropyrazine-3-sulfenamide in 25 milliliters of chloroform was added to a rapidly stirring mixture of 0.69 gram (0.25 millimole) of sodium bicarbonate and the resulting mixture cooled to 0° C. To the cooled solution, a solution of gram (5.5 millimole) of m-chloroperbenzoic acid in 25 milliliter of chloroform was added dropwise over a 15 minute period. After completion of the addition, stirring was continued for 15 hours. At the end of this period, chloroform layer was separated from the aqueous layer, dried over anhydrous potassium carbonate, and subjected to reduced pressure to remove the solvent and to recover as residue an oil which solidified on standing. The latter was purified by crystallization from ethanol to obtain the desired N-benzylidene-2-chloropyrazine-3-sulfinamide product, m.p. 113°-114° C. Elemental analyses were as follows:
Reaction SMILES: [N:1]1([C:7](=[O:28])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=C[C:36]2[N:41](O)N=[N:39][C:37]=2C=1.Cl.NCC#N.CN1CCOCC1>>[C:37]([CH2:36][NH:41][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:25])[F:26])(=[O:15])=[O:16])[CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:28])#[N:39]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1C(F)(F)F
Agent: Cl
Agent: N#CCN
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: N#CCNC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture comprised of 4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzylsulfonylmethyl)-butyric acid (200 mg, 0.47 mmol), prepared as in reference 5, EDC (200 mg, 1.05 mmol), HOBt (200 mg, 1.3 mmol), and aminoacetonitrile hydrochloride (150 mg, 1.6 mmol) was treated with dichloromethyl (4 mL) and 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The product was crystallized from ethyl acetate/hexane to yield N-cyanomethyl-4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzyl-sulfonylmethyl)-butyramide (156 mg) as a yellowish solid; 1H NMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H), 7.81–7.57 (m, 4H), 4.74 (d, J=14.5 Hz, 1H), 4.67 (d, J=14.5 Hz, 1H), 4.13 (d, J=5.5 Hz, 2H), 3.63–3.26 (m, 11H), 2.75 (dd, J=6.4 Hz, J=16.8 Hz, 1H), 2.65 (dd, J=6.2 Hz, J=16.8 Hz, 1H); MS: (M++1) 462;