Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)C(=[C:9]([O:11][CH3:12])[CH:10]=1)C=O.[C:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1CCCCC1.C(#N)C>[C:14]([C:22]1[C:23](=[O:24])[O:25][C:26]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:27]=2)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1cc(O)c(C=O)c(OC)c1
Solvent: C1CCNCC1
Solvent: CC#N
Product: COc1cc(OC)c2cc(C(=O)c3ccccc3)c(=O)oc2c1

Procedure:
A mixture of 18.2 g 4,6-dimethoxysalicylaldehyde, 20.0 g ethyl benzoylacetate, 20 ml acetonitrile and 30 drops piperidine was heated gently on a hot plate for 45 minutes. After cooling the product was collected and recrystallized twice from acetonitrile and once from benzene containing a small amount of acetonitrile. m.p. 178° C.-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:14])[C:11]([CH3:13])=O>>[CH2:20]([CH:17]([CH2:18][CH3:19])[CH2:16][O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH3:21]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCC(CC)COC(=O)C(C)=O
Product: CCC(CC)COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and 2-ethylbutyl pyruvate (prepared by following General Procedure AO above using 2-ethylbutanol (Aldrich) in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:30][O:31][CH:32](OC)[N:33](C)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:27])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][C:32]([O:31][CH3:30])=[NH:33])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(=N)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
In a solution of 0.09 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methoxymethyl benzoic acid amide in 2 mL of tetrahydrofuran, 0.05 g of N,N-dimethylformamide dimethylacetal was added, and stirred at room temperature for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 2 mL of tetrahydrofuran, a solution of 0.02 g of methoxyamine hydrochloride in 2 mL of water was added dropwise. After the completion of the addition dropwise, it was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, 5 mL of water was added in the residue, and extracted with ethyl acetate (10 mL×1). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:4) to obtain 0.07 g of the aimed product as white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:34]6[CH:35]=[N:36][CH:37]=[CH:38][N:33]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2cnccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cnccn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.16 g, 0.369 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.05 g, 0.369 mmol, 1 eq), EDCI.HCl (0.07 g, 0.369 mmol, 1 eq), HOBT (0.05 g, 0.369 mmol, 1.0 eq) and TEA (0.15 ml, 1.107 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water, and organic layer separated and washed with water. The organic layer was dried over Na2SO4 and concentrated. The crude product obtained was purified by Prep. HPLC. 1H NMR (400 MHz, CD3OD): δ 1.43-1.46 (m, 2H), 1.72-1.75 (m, 2H), 2.37 (s, 3H), 2.95 (s, 3H), 4.08 (s, 3H), 7.161 (s, 1H), 7.25-7.30 (m, 2H), 7.35 (dd, J=2, 8.4 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.96-7.99 (m, 2H), 8.36 (d, J=2.8 Hz, 1H), 8.520-8.531 (m, 1H), 8.72 (d, J=1.2 Hz, 1H). LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=2[CH3:29])=[CH:33][CH:32]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cc1
Yield: 68 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (4-methylphenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 68%. Melting point: 194-195° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([Br:27])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCc2cc(Br)sc2CC1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
The product of Example 1, step (d) (80 mg, 0.35 mmol) was dissolved in 2 mL of 1:1 CHCl3:HOAc and treated with NBS (62 mg, 0.35 mmol). After 15 minutes, the reaction was concentrated to dryness, dissolved in a minimal amount of EtOAc and filtered through a pad of silica gel. The filtrate was evaporated to give 105 mg of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H][H]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCC#Cc1ccc(Br)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCCCc1ccc(Br)cc1
Yield: 81.1 %

Procedure:
To a solution under inert gas of 36.4 g of 3-(4-bromophenyl)-2-propynol (stage A) in 200 ml of ethanol at 5% of toluene, is added 200 ml of toluene, 7.9 g of Wilkinson's reagent and hydrogen at 1900 mbar for 5 hours. It is evaporated at reduced pressure until the obtainment of 45.9 g of raw product that is purified by chromatography on silica by eluting with the compound CH2Cl2/AcOEt 95/5. 30.1 g of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCC2)cn1
Yield: 81 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using cyclopentylamine (1 M in DMF) instead of methylamine, to the title compound (98 mg, 81%) which was obtained as a white solid. MS: m/e=378.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH2:17][CH2:16]2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:25]1([NH:24][C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:4]3[CH:3]=[C:2]([Br:1])[CH:11]=[C:10]4[C:5]=3[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]4)[CH2:16][CH2:17]2)=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1CCN(Cc2cc(Br)cc3[nH]c(=O)c(=O)[nH]c23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)C1CCN(Cc2cc(Br)cc3[nH]c(=O)c(=O)[nH]c23)CC1
Reaction time: 0.5 h

Procedure:
382 mg (1 mmol) of N-(7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-piperidine-4-carboxylic acid (Example 6), 186 mg (2 equiv.) of aniline, 480 mg (2.5 equiv.) of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and 384 mg (2.5 equiv.) of 1-hydroxy-benzotriazole are stirred at 20° C. in dried dimethylformamide for 48 hours. The mixture is poured into water and extracted three times with 100 ml of dichloromethane. The organic phases are combined and concentrated by evaporation. The residue is dissolved in 30 ml of dichloromethane and the solution is stirred for 30 minutes. The white solid is filtered off, washed with dichloromethane and dried.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17]>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=Cc1ccccn1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccccn1)C(=O)OCC

Procedure:
Diethyl β-(2-pyridyl)-ethylmalonate was prepared in the manner described by V. Boekelheide and S. Rothchild, JACS, 71, 879 (1949). Briefly, diethyl malonate (375 g, 2.35 moles) was added to a solution of sodium ethoxide (23 g of sodium in 225 mL of absolute alcohol). To the boiling mixture, freshly distilled 2-vinylpyridine (106 g, 1.0 mole) in 175 mL of absolute alcohol was added slowly. After the mixture had boiled under reflux for two hours, the alcohol was removed by distillation and the residue was acidified with dilute hydrochloric acid. The unreacted malonic ester was extracted with ether, the aqueous phase was made basic with dilute sodium hydroxide, and the basic organic layer was extracted with ether. After the ethereal solution had been dried over Drierite, the ether and recovered 2-vinylpyridine (boiling point 58° C. at 16 mm) were removed in vacuo.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15]CC)=[O:14].Cl[Sn]Cl.[CH3:21][CH2:22]O>>[CH2:21]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[C:7]([F:8])[C:2]=1[F:1])[C:13]([OH:15])=[O:14])[CH3:22]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(F)c1F
Reactant: CCO
Agent: Cl[Sn]Cl
Product: CCC(C(=O)O)c1ccc(N)c(F)c1F
Reaction time: 18 h
Yield: 38 %

Procedure:
To a stirred solution of ethyl 2,3-difluoro-4-nitrophenylacetate (5.85 g, 23.9 mol) in EtOH (100 mL), was added SnCl2 (16.1 g, 71.6 mmol) at rt. The stirring was continued for 18 hours at reflux. After removal of the solvent, the residue was dissolved in CHCl3 (100 mL) and poured into ice water-4M NaOH (40 mL of 4M NaOH in 300 mL of ice-water), extracted with CHCl3 (100 mL×2), dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was chromatographed on silica gel (middle pressure chromatography system YAMAZEN YFLC-5404, linear gradient of hexane-EtOAc from 9:1 to 7:3, φ50 mg×500 mg, 15 ml/min) to give ethyl 4-amino-2,3-difluorophenylacetic acid (1.94 g, 38%) as a colorless oil. 1H-NMR (CDCl3) δ 1.25 (t, J=7.3 Hz, 3 H), 3.55 (d, J=1.0 Hz, 2 H), 3.78 (br s, 2 H), 4.15 (dd, J=7.2 Hz, 14.2 Hz, 2 H), 6.49 (dt, J=1.8, 8.2 Hz, 1 H), 6.78 (m, 1 H); MS (FAB) m/z 216 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[N:3]=1.[Cu][C:11]#[N:12]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1C#N

Procedure:
A mixture of 2-amino-5-bromo-6-methylpyridine (20.0 g, 0.107 mol) (Maybridge) and copper (I) cyanide 11.0 g, 0.123 mol) in DMF (25 ml) was heated to reflux for 4 h. The DMF was evaporated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium cyanide solution. The organic layer was washed with 10% sodium cyanide solution and brine, dried (Na2SO4) and evaporated in vacuo to a brown solid. This was dissolved in a minimum amount of ethyl acetate and the product was precipitated by adding hexanes. The mixture was filtered to give the title compound as a brown powder:
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:34]([CH3:36])[CH3:35])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)Br
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)C)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless oil (54%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4]
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2ncnc(C3C(=O)Nc4cc(C#N)ccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
Sodium hydride (100 mg, 2.6 mmol) was added to a solution of 6-cyanooxindole (350 mg, 2.2 mmol) in dry degassed DMF (10 ml) under argon and the suspension stirred for 30 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (200 mg, 0.74mmol), (prepared as described for the starting material in Example 2), in dry degassed DMF (2 ml) was added dropwise and the reaction mixture was heated at 60° C. for 2 hours. The mixture was allowed to cool and the DMF was removed by evaporation and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml×3). The organic extracts were combined, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by flash column chromatography eluting with methylene chloride/methanol/ammonia (99/1/1 and then 95/5/1). The purified solid was triturated in hot ether and collected by filtration and then triturated in hot methylene chloride/methanol (1/1), collected by filtration and dried to give 4-(6-cyanooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (84 mg, 29%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[C:14]1([NH:20][C:21]2[N:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:23][C:22]2[C:21]([NH:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: O=Cc1cccnc1Nc1ccccc1
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cccnc2Nc2ccccc2)cc1OC
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
To a solution of 3,4-dimethoxyacetophenone (182 mg, 1.01 mmol) in methanol (5 mL) was added 2N Ba(OH)2solution (2 mL) and stirred for 5 minutes. Then added 2-(phenylamino)nicotinaldehyde (200 mg, 1.01 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture was acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6b) (328.5 mg, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([S:32]([N:35](CC3C=CC(OC)=CC=3OC)[C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1.O1CCOCC1>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>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:22]1[C:31]2[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)nccc2c1
Temperature: 100 °C
Yield: 22.4 %

Procedure:
A pressure vessel was charged with (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (56.5 mg, 0.252 mmol), potassium carbonate (145 mg, 1.048 mmol), 1-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.210 mmol), tetrakis(triphenylphosphine)palladium(0) (24.23 mg, 0.021 mmol), dioxane (1398 μl) and water (699 μl). The reaction vessel was swept with nitrogen, sealed with a cap and then heated in a microwave at 100° C. for 30 minutes. The mixture was cooled to room temperature. The organic layer was separated by pipet and then purified by reverse phase HPLC (Column: Gemini 150×30 mm, 5 μm, Phenomenex, Torrance, Calif., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing pure product were dried under a vacuum to provide 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (22 mg, 0.047 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.57 (br. s., 1H) 3.63-3.80 (m, 1H) 7.70 (d, J=8.82 Hz, 1H) 7.79 (d, J=7.90 Hz, 1H) 7.86-7.96 (m, 1H) 8.12 (s, 1H) 8.25 (d, J=5.61 Hz, 1H) 8.47 (s, 1H) 8.65 (d, J=1.49 Hz, 1H) 8.77 (d, J=5.73 Hz, 1H); m/z (ESI) 471.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.NN.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: NN
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2
Temperature: 150 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
A mixture of 5-methylisatin (15.0 g) and 60 ml of hydrazine hydrate was stirred at 140-160° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into 300 ml of ice water and acidified to pH 2 with 6 N hydrochloric acid. After standing at room temperature for 2 days, a precipitate formed which was collected by vacuum filtration, washed with water and dried under vacuum to give 6.5 g (47% yield) of 5-methyl-2-oxindole.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1>>[O:29]1[C:33]2([CH2:38][CH2:37][N:36]([C@H:2]3[CH2:19][C@@:18]4([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]5[C@@H:17]4[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@H:9]5[CH2:10][C@H:11]([N:22]5[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]5)[C@@H:12]4[OH:21])[CH2:4][C@@H:3]3[OH:1])[CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Reactant: C1CC2(CCN1)OCCO2
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Yield: 85.9 %

Procedure:
2α,3α-Epoxy-16β-(4-hydroxy-1-piperidinyl)-5α-androstane-17β-ol is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to obtain the title compound in a yield of 85.90%, m.p.: 253°-255° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][O:18][CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CCOC(C)=O
Product: COC[C@@H](NC(=O)[C@@H]1[C@@H]2C[C@@H]2CN1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (1R,2S,5S)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc): 0.45; MS (UPLC/MS): 413.3/415.3 [M+H]+, 457.3 [M+HCOO]−; tR (HPLC conditions a): 3.64 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C.O>[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])=[CH:4][CH:5]=1)=[CH2:10]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Yield: 46 %

Procedure:
To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resultant reaction mixture was heated at 70° C. for 16 h. The reaction mixture was diluted with H2O and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Recrystallization from CH3OH afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm−1.