Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:10]>>[CH:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:16])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCCCCCCO
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CCCCCCCOC(=O)c1ccc(C=O)cc1

Procedure:
The title compound was prepared through a condensation between 1-heptanol and 4-formylbenzoic acid. 1H NMR (500 MHz, CDCl3): δ 10.10 (s, 1H), 8.20 (d, J=8.2, 2H), 7.95 (d, J=8.2, 2H), 4.35 (t, J=6.8, 2H), 1.75-1.85 (m, 2H), 1.40-1.50 (m, 2H), 1.25-1.40 (m, 6H), 0.89 (t, J=7.0, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][OH:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.C1COCC1>[Si:20]([O:14][CH2:13][C@H:2]([NH2:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: N[C@@H](CO)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of D-Tryptophanol (1.024 g) and imidazole (403 mg) in DCM (40 ml) and THF (8 ml) was added a solution of tert-butyldimethylsilyl chloride (0.852 g) in DCM (5 ml) dropwise. The reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and the reaction mixture was extracted with dichloromethane. The aqueous phase was washed with dichloromethane and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.
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]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1.Cl>ClCCl.CO>[ClH:1].[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:14](=[O:16])[C:13]#[C:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[Cl:1])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCCN(CCOc1ccc(N)cc1OC)CC1CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCN(CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 185 mg (0.66 mmol) of 4-[2-(cyclopropylmethylpropylamino)ethoxy]-3-methoxyphenylamine. Yield: 180 mg (59% of theory); melting point: 185° C.-188° C.; C26H28ClF3N2O3 (M=508.96)*HCl; calc.: molecular ion peak (M+H)+: 509/511 (Cl); found: molecular ion peak (M+H)+: 509/511 (Cl); Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1[CH:17]=[C:16](Cl)[C:15]([N+:19]([O-])=O)=[CH:14][C:13]=1[N+:22]([O-])=O)[CH3:8].C(O)(=O)C>ClCCl.[Zn]>[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1[CH:17]=[C:16]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:15]([NH2:19])=[CH:14][C:13]=1[NH2:22])[CH3:8]
Reactant: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(N2CCCCC2)c(N)cc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Piperidine (120 mg) was added to a solution of (5-chloro-2,4-dinitro-phenyl)-acetic acid ethyl ester (150 mg) in dichloromethane (5 mL) and the resulting mixture was stirred at room temperature for 10 minutes. Glacial acetic acid (0.3 mL) and zinc dust (1 scoop) were added and the reaction mixture was stirred at room temperature for 20 minutes. The resulting mixture was filtered through a CELITE™ pad, the filter cake was washed with dichloromethane and the filtrate was evaporated under reduced pressure. The residue was then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give (2,4-diamino-5-piperidin-1-yl-phenyl)-acetic acid ethyl ester. This material was dissolved in toluene (2.5 mL) and heated at 150° C. in a microwave reactor for 10 minutes. The reaction mixture was then cooled, evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH, 95/5) to give 30 mg of 6-amino-5-piperidin-1-yl-1,3-dihydro-indol-2-one. MS=232 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O1CCOCC1.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>Cl.O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH2:16][C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(Cc1c(O)cccc1O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 550 g. of resorcinol in 1 l. of dioxane were added 600 g. of acetophenone and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated with stirring for 3 hours and then poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])#[N:23].C(N(CC)C(C)C)(C)C>ClCCl>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31])#[N:23]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C#N

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-cyanobenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 2-cyano-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 505.8 ([M+NH4]+)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.Cl[C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1>>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=[C:15]([O:11][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=3)[CH:25]=[C:19]12
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(C(F)(F)F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(4-(trifluoromethyl)phenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:15][CH3:16])[C:10](OCC)=[O:11])=[CH:5][CH:4]=1.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:15][CH3:16])[C:10]([NH:19][NH2:20])=[O:11])=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)C(OC)c1ccc(N(C)C)cc1
Solvent: O
Solvent: CCO
Product: COC(C(=O)NN)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 38.8 %

Procedure:
To a solution of ethyl 2-(4-(dimethylamino)phenyl)-2-methoxyacetate (0.675 g, 2.84 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (0.8 mL, 16.4 mmol) and the mixture was heated at reflux for 22 hours. Additional hydrazine hydrate (1.0 mL, 20.6 mmol) was added and the heating continued for 7 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The solid product was stirred with hot diethyl ether then hexanes were added. After cooling to room temperature, the solids were collected on a Büchner funnel and rinsed with 50% diethyl ether-hexanes then dried under vacuum to give 2-(4-(dimethylamino)phenyl)-2-methoxyacetohydrazide as an orange solid (0.246 g). Additional product was isolated from the mother liquor by chromatography (80-100% EtOAc-hexanes, then 5% methanol-EtOAc) to give an off-white solid (0.173 g, 66% yield total).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:19]3[C:11](=[CH:12][C:13]4[CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:30][C:29]=6[CH3:38])=[CH:24][CH:23]=5)=[O:21])[C:17]=4[CH:18]=3)[O:10][CH2:9]2)[CH2:5][CH2:4]1)[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)(Cl)Cl>[C:39]([NH:37][NH:36][C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:20]([N:16]3[C:17]4[CH:18]=[C:19]5[C:6]6([CH2:9][O:10][C:11]5=[CH:12][C:13]=4[CH2:14][CH2:15]3)[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]6)=[O:21])=[CH:27][CH:26]=2)=[C:29]([CH3:38])[CH:30]=1)=[O:35])(=[O:41])[CH3:40]
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(C(=O)NN)cc2C)cc1)CC3
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(C(=O)NNC(C)=O)cc2C)cc1)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 2623.7 %

Procedure:
To a stirred solution of 1'-ethyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E61, 1.00 g, 1.96 mmole) in chloroform (30 ml), acetic anhydride (5.76 ml, 0.06 mmole) was slowly added. The solution was stirred at room temperature for approximately 1 hour, then concentrated in vacuo. Toluene was used to azeotrope out the excess acetic anhydride. The residue was dissolved in chloroform, washed with 10% Na2CO3 solution and the organic phase dried (Na2SO4), then concentrated in vacuo. The residue beige solid was chromatographed on silica gel, eluting with 0-12% methanol in chloroform to afford the title compound as a yellow solid (0.87 g, 80%) m.p. 154-157° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[CH3:21][O:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccs1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(NC(=O)c3cccs3)nc2n1
Temperature: 4 °C
Yield: 77.9 %

Procedure:
The procedure is similar to that described in Example 1, starting with 2-thiophenecarboxylic acid (14 g) N,N'-carbonyldiimidazole (17.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (12.3 g). The product produced by precipitation in water (19.5 g; m.p. 216° C.) is dissolved in boiling ethanol (750 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-2-thiophenecarboxamide (15.6 g) is produced, m.p. 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH:12]([Mg]Cl)([CH3:14])[CH3:13].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([CH:12]([CH3:14])[CH3:13])=[CH:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=C1CCc2cc(Cl)ccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1=CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-chloro-1-indanone (3.59 g) in anhydrous tetrahydrofuran (40 ml) was added to a solution of isopropyl magnesium chloride (103 ml, 2M ethereal solution) under nitrogen at a rate to produce gentle refluxing. After the addition, the reaction solution was further stirred at room temperature for 11/4 hr, then poured into water (200 ml) and extracted with diethyl ether (3×150 ml). The combined ether solutions was washed with water, and condensed to an oil. This oil dissolved in benzene (250 ml) with a catalytic amount of p-toluenesulfonic acid was refluxed for 1.5 hr and then poured into water (200 ml). A few drops of diethylamine were added. The aqueous solution was separated and extracted with diethyl ether (3×100 ml). The combined organic phases were washed sequentially with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, then dried (MgSO4) and condensed under reduced pressure. The residue was purified on a flash column (eluted with 5% ether in hexane) to give 6-chloro-3-isopropyl-1H-indene (2.94 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC=CC=1.NC1C=CC(C(OC)=[O:28])=C(Br)C=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:11]=[C:10]([OH:28])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: COC(=O)c1ccc(N)cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: Nc1ccccc1
Product: COC(=O)c1ccc(O)cc1Br
Temperature: 90 °C
Reaction time: 5 h

Procedure:
2-Bromo-4-nitrobenzoic acid (6.2 g, 25.3 mmol) was dissolved in MeOH (120 mL), and SOCl2 (5.5 mL, 75.9 mmol) was added dropwise at 0° C. The reaction mixture was refluxed for 6 h. The reaction solvent was concentrated to dryness. Residual SOCl2 was removed by co-evaporation with CH2Cl2 (×3). The solid was dried under vacuum to afford methyl 2-bromo-4-nitrobenzoate in 99.5% (6.52 g) yield as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (1H, s, Ar), 8.21 (1H, d, J=8.4 Hz, Ar), 7.91 (1H, d, J=8.4 Hz, Ar), 3.97 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.2, 149.2, 137.9, 131.7, 129.1, 122.1, 122.0, 53.1; MS (ESI) m/z Calcd for C8H6BrNO4 (M+): 259.0, Found: 260.1 (M+H+). Next, the nitro group of methyl 2-bromo-4-nitrobenzoate (6.38 g, 24.6 mmol) was chemoselectively reduced with 5 nCl2.2H2O (27.8 g, 123.2 mmol) in a manner similar to that described for compound 6 to deliver methyl 4-amino-2-bromobenzoate in 96.0% (5.41 g) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d, J=8.8 Hz, Ar), 6.90 (1H, d, J=1.6 Hz, Ar), 6.55 (1H, dd, J=8.8 Hz, 1.6 Hz, Ar), 4.06 (2H, s, NH2), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 150.4, 133.6, 124.1, 119.7, 119.6, 112.7, 51.8; MS (ESI) m/z Calcd for C8H8BrNO2 (M+): 229.0, Found: 230.1 (M+H+). Finally, a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) was added to methyl 4-amino-2-bromobenzoate (1.23 g, 5.38 mmol) and the resulting suspension was heated to 90° C., then stirred for 5 h at this temperature. The reaction mixture was cooled to 0° C. and a solution of NaNO2 (384 mg, 5.57 mmol) in H2O (5 mL) was added dropwise, then the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) that had been preheated to 90° C. The reaction mixture was stirred at 90° C. for 1 h, and then allowed to cool. The reaction mixture was partitioned between EtOAc (200 mL) and aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (35% EtOAc in hexanes) to afford compound 10 in 41.1% (508 mg) yield as a light brown solid. 1H-NMR (CDCl3, 400 MHz) δ 7.76 (1H, d, J=8.8 Hz, Ar), 7.09 (1H, s, Ar), 6.75 (1H, d, J=8.8 Hz, Ar), 3.84 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 166.2, 160.3, 133.5, 123.4, 122.1, 121.4, 114.3, 52.1; MS (ESI) m/z Calcd for C8H7BrO3 (M+): 230.0, Found: 231.0 (M+H+).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([NH:14][C@H:15]([C:23]([OH:25])=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][NH:38][C:23](=[O:25])[C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:14][C:12](=[O:13])[C@@H:11]1[CH2:26][CH2:27][CH2:28][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:29])=[CH:6][CH:5]=1)(=[O:9])=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)NOCc2ccccc2)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-prolyl-L-phenylalanine was coupled to O-benzylhydroxylamine using the procedure described in Method 3 to give the title compound as a white solid, mp=127-130° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([OH:8])[CH:7]=1.Br[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([O:8][CH:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: Oc1cc(I)ccc1OCCN1CCCC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc(I)ccc1OCCN1CCCC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 0.15 g (0.45 mmol) of 5-iodo-2-(2-pyrrolidin-1-ylethoxy)phenol (Example 33.1c), 52 μL (0.55 mmol) of 2-bromopropane, and 186 mg (1.35 mmol) of potassium carbonate in 2 mL of acetonitrile was stirred for 2 hours at 75° C. The reaction mixture was diluted with water and the aqueous phase exhaustively extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 77 mg (46% of theoretical); C15H22INO2 (M=375.245); calc.: molpeak (M+H)+: 376; found: molpeak (M+H)+: 376; HPLC-MS: 5.86 minutes (method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([OH:23])(=[O:22])[CH3:21].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=[C:21]([C:20]([OH:23])=[O:22])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C(=O)O)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To 430 mg of 3-(3-fluorophenyl)-7-methyl-1H-indazole-5-carbonitrile were sequentially added 6.0 ml of glacial acetic acid, 2.0 ml of water and 2.0 ml of concentrated sulfuric acid, followed by stirring at 100° C. for one day. After standing to cool, the reaction mixture was diluted with 20 ml of water, and the resulting crystals were collected by filtration. The crystals were sequentially washed with water and diethyl ether, to give 360 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[F:27][C:28]1([F:33])[CH2:30][CH:29]1[CH:31]=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([C:16](=[CH:31][CH:29]3[CH2:30][C:28]3([F:33])[F:27])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=CC1CC1(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(=CC2CC2(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: -20 °C
Reaction time: 3 h

Procedure:
At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 10 ml of THF, and the mixture was stirred for another 10 min 488 mg (4.60 mmol) of 2,2-difluorocyclopropanecarbaldehyde were then added, and after a further 10 min the mixture was warmed to −20° C. After 3 h at −20° C., the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little dichloromethane and purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 240 mg (purity 78%, 30% of theory)
Reaction SMILES: C([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=O)C.[OH-].[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:12]2[C:8](=[CH2:4])[CH2:7][O:6][C:5]2=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C=C1COC(=O)C1c1ccccc1

Procedure:
The reaction was repeated using 3-acetyl-dihydro-2(3H)-furanone, sodium hydroxide and benzaldehyde to produce 3-phenyl methylene-dihydro-2(3H)-furanone. The crude yellow solid obtained from the reaction was recrystallized from chloroform to recover 3-phenylmethylene-dihydro-2(3H)-furanone, a yellow crystalline solid melting at 116° C. Proton and carbon nuclear magnetic resonance spectra for the product were as follows:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([F:12])[CH:8]=[C:7]([OH:13])[C:6]=2[C:5]([CH2:14][CH2:15][OH:16])=[CH:4]1)[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:13][CH3:17])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][CH2:15][OH:16])=[CH:4]1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCn1cc(CCO)c2c(O)cc(F)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1cc(CCO)c2c(OC)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
39-2 (318 mg, 1.43 mmol) was dissolved in DMF (5 mL) and then potassium carbonate (236 mg, 1.71 mmol) and methyl iodide (98 uL, 1.56 mmol) were added. The reaction mixture was stirred at room temperature overnight, concentrated under vacuum and then water added. A solid was filtered to afford 39-3 (313 mg, 90%) as a light purple solid. LCMS: calc 326.2. found 327.1 [MH]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].[Br:19][CH2:20][C:21](Cl)=[O:22]>CN(C)C=O>[Br:19][CH2:20][C:21]([N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)CBr
Reactant: c1ccc(NCc2cccs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CBr)N(Cc1cccs1)c1ccccc1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
To a 0° C. stirring suspension of the N-(thiophen-2-ylmethyl)aniline (3.51 g, 18.53 mmol) and sodium bicarbonate (1.71 g, 20.38 mmol) in dimethylformamide (15.0 mL), it was added bromoacetyl chloride (1.54 mL, 18.53 mmol). The ice bath was removed and the flask was attached to a bubbler to allow gas evolution and expansion. The reaction was stirred overnight at room temp. Most of the volatiles were evaporated in vacuo, then the residue was taken up in dichloromethane and was washed with water first and then brine. The resulting organic layer was dried over MgSO4(s) and concentrated. The obtained crude was absorbed under vacuum on Florisil with the aid of DCM (dry load). The obtained dispersion was purified by column chromatography (Biotage system, hex:EtOAc 1-20% gradient over 30 CV, 40 g Silicycle silica column) The collected fractions were evaporated to afford 4.51 g of 2-bromo-N-phenyl-N-(thiophen-2-ylmethyl)acetamide (14.55 mmol; 78%), which was judged more than 97% pure by 1H-NMR analysis.