Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)C1C=CC=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:18]=[CH:19][CH:20]=[CH:3][CH:4]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2)cc1OC

Procedure:
3,4-Dimethoxybenzophenone was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (2 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and benzoyl chloride (1.8 mL, 15.5 mmol). The crude mixture was purified by flash column chromatography (silica gel, 3% ethyl acetate/methylene chloride) to yield 3.44 g (93%) of the product as a white solid: mp 99-100° C.; 1H NMR (CDCl3) δ 7.82-7.30 (m, 7 H), 6.95-6.85 (m, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ 195.5, 153.0, 149.0, 138.2, 131.8, 130.2, 129.6, 128.1, 125.4, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C15H14O3. Theoretical: C, 74.36; H, 5.82. Found: C, 74.21; H, 6.01.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[O:7])=[CH:4][CH:3]=1.[CH3:19]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([O:16][CH3:19])=[O:15])=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(Br)cc1)[C@H]1CCCC[C@H]1C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
To a solution of cis-2-(4-bromobenzoyl)-1-cyclohexanecarboxylic acid (4.0 g, 12.85 mmol) in MeOH (50 mL) was added 2,2-dimethoxypropane (2.01 g, 19.28 mmol) and HCl (4.0 M in dioxane, 1.20 mL). The resulting solution was stirred at 40° C. for 3 days, and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 3 to 6% ethyl acetate in hexanes to afford methyl cis-2-(4-bromobenzoyl)cyclohexanecarboxylate (1.76 g, 42%). LC-MS ret. time 3.40; m/z 326 (MH+); 1H NMR (400 MHz, CD2Cl2) δ 1.35-1.51 (m, 3H), 1.72-1.86 (m, 2H), 1.91-2.05 (m, 2H), 2.11-2.20 (m, 1H), 2.74 (m, 1H), 3.58 (s, 3H), 3.82 (q, 1H), 7.62 (m, 2H), 7.73 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]#[N:13]>CCOC(C)=O.CCO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH2:11][C:12]#[N:13])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(CC#N)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1CC#N
Yield: 77 %

Procedure:
2-(2-Methyl-3-nitrophenyl)acetonitrile (Askam, V. et al. J. Chem. Soc. C (1969)1935–1936;) was hydrogenated over 5% palladium-charcoal 50 mg in EtOAc/EtOH 1:1 (14 ml) for three hours. The mixture was filtered through celite, and the filtrate was concentrated to give the title compound 77 mg (77%) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]([CH:18]([OH:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[C:15]([OH:17])=[O:16].[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Pd]>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH:18]([OH:28])[CH:14]([CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[C:15]([OH:17])=[O:16])=[CH:22][CH:23]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2cc3ccccc3o2)cc1
Temperature: 150 °C
Yield: 12.4 %

Procedure:
A solution of 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-iodophenyl)pentanoic acid (25 mg, 50 μmol) in dimethylformamide (1.0 mL) was added in one portion to a mixture of -benzofuran-2-ylboronic acid (11 mg, 70 μmol) and fibrecat FC1001 (2.71% Pd; 20 mg, 5.0 μmol) in a Smith microwave reaction vial. Cesium carbonate (41.0 mg, 125 μmol) was added and the vial capped. The crude reaction mixture was heated at 150° C. for 15 min using a Smith Synthesiser microwave reactor. On cooling the vial was opened and the contents partitioned between methanol/dichloromethane (10:90; 10 mL) and aqueous hydrochloric acid solution (2.0 M; 10 mL). The organic phase was separated and filtered through a Whatman 5 μM filter tube, washing the filter cake with methanol (2×1 mL). The filtrate was evaporated and the resulting residue was purified using mass directed auto-preparative reverse phase HPLC to give the title compound (3.0 mg, 12%) as a pale yellow solid. LC/MS: 3.69 min; z/e 484, calcd (M+1) 484. 1H NMR (400 MHz: DMSO-d6): 7.80 (6H), 7.65 (2H), 7.30 (5H), 3.65 (1H), 3.60 (2H), 2.75 (1H), 2.55 (1H), 2.40 (1H major), 2.25 (1H minor), 1.85 (2H), 1.65 (2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-aspartic acid dimethyl ester hydrochloride (2.0 g, 10 mmol) was dissolved in dichloromethane (30 ml), phenyl chloroformate (1.3 mL, 11 mmol) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1CC.[SH:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1
Reactant: Sc1ncccn1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCSc1ncccn1

Procedure:
Using the general method of Example 20 Part A, 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.30 mmol) was reacted with 2-mercaptopyrimidine (0.59 g, 5.3 mmol) to provide 1.0 g of 2-ethyl-1 μm-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, m.p. 182-185° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C.C(Cl)Cl>[Si:14]([O:13][CH2:12][CH2:11][CH2:10][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1CCNC1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a stirred solution of 2-imidazolidone (5.0 g, 60 mmol) in DMF (100 mL) was added NaH (2.4 g, 60% in mineral oil, 60 mmol). The reaction was then heated to 50° C. and was allowed to stir until bubbling of H2 ceased (˜1 hour). To the mixture was added dropwise (3-bromopropoxy)-tert-butyldimethylsilane (13.5 mL, 60 mmol). The reaction mixture was allowed to stir for 3 hours at 50° C. After 3 hours, the reaction was cooled to room temperature and condensed under reduced pressure and then dissolved in DCM (250 mL) and washed with 1N HCl (500 mL), water (500 mL), NaCl (sat.) (500 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography (10% MeOH/DCM) to afford the title compound in 45% yield (6.9 g, 26.7 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38](O)=[O:39])[C:33]3[C:28](=[CH:29][C:30]([CH3:41])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[CH:60]1([NH:63][C:64]([C@@H:66]2[CH2:70][CH2:69][CH2:68][NH:67]2)=[O:65])[CH2:62][CH2:61]1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C:64](=[O:65])[NH:63][CH:60]3[CH2:61][CH2:62]3)=[O:39])[C:33]3[C:28](=[CH:29][C:30]([CH3:41])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3n2)CC1
Reactant: O=C(NC1CC1)[C@@H]1CCCN1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CC3)c3ccc(C)cc3n2)CC1
Temperature: 50 °C

Procedure:
To a solution of 1 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 12 ml of DMF, 392 mg of EDC, 376 mg of pentafluorophenol and 392 mg of NEM was added and the reaction mixture was warmed to 50° C. for 2 h. Then, after cooling to RT, 334 mg of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 201 mg of NEM in 5 ml of DMF was added. After 1 h the reaction mixture was diluted with water and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 1.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[O-:9][Mn](=O)(=O)=O.[K+].[OH2:15]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:9])=[O:15])[CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(Br)ccn1
Reactant: O
Agent: [K+]
Product: O=C(O)c1cc(Br)ccn1

Procedure:
A stirred solution of pyridyl bromide 153 (5.03 g, 29.0 mmol) in water (130 mL) is treated at RT with KMnO4 (4.72 g, 29.5 mmol) in one portion then heated to reflux 1.5 h. At this juncture more KMnO4 is added (4.72 g, 29.5 mmol) and the solution heated at reflux a further 2 h. Another portion of KMnO4 is then added (9.43 g, 59 mmol), the reaction heated at reflux a further 3 h then filtered whilst still hot, washing the isolated solids with boiling water (200 mL). The aqueous filtrate is then concentrated in vacuo to approximately 40 mL, acidified to pH 4 by careful addition of 1 M HCl and the resultant white precipitate isolated by filtration. The filtrate is then reduced in vacuo to approximately 10 mL and the forthcoming precipitate also isolated by filtration. Combining these two isolated precipitates gives the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:4])=[O:3].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[SH:25].C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1.[Na+].[Cl-]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25][C:11]1[C:10]([O:15][CH3:16])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]2
Reactant: Fc1ccc(S)c(F)c1
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 2-methanesulfonyl-6-methoxy-quinoline (237 mg , 1 mmole) and 2,4-difluorobenzenethiol (296 mg ,2 mmoles) was treated with PIFA (645 mg, 1. 5 mmoles) and stirred for 30 min. The solution was poured into dilute NaCl solution and extracted with ethyl acetate (EtOAc). The organic layer was dried (MgSO4) and evaporated. The resulting oil was crystallized to yield 5-(2,4-difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 101.; ([M+H]+)=382 The yield is typically 80–90%.
Reaction SMILES: [C:1]1([CH2:11][NH:12][S:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:26]C(=O)C)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)CC.[ClH:34]>O>[ClH:34].[NH2:26][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH:23]=[CH:24][CH:25]=[C:16]2[S:13]([NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:15])=[O:14]
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)NCc3cccc4ccccc34)cccc12
Agent: Cl
Solvent: CCCO
Solvent: O
Product: Nc1cccc2c(S(=O)(=O)NCc3cccc4ccccc34)cccc12
Temperature: 25 °C

Procedure:
N-[5-[[[(1-naphthalenyl)methyl]amino]sulfonyl]-1-naphthalenyl]acetamide (226 mg, 0.56 mmol) was suspended in a mixed solution of 1-propanol (8 ml), concentrated hydrochloric acid (1 ml) and water (1 ml), and the mixture was refluxed for 1 hour. The crystal precipitated by cooling of the reaction mixture to room temperature was filtered and washed with the mixed solvent of 1-propanol/diisopropyl ether under reflux to give the title compound an a white crystal (201 mg, 90.8%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[S:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2O)[CH:14]=[CH:13]1.P(CCCC)(CCCC)CCCC>>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[CH:13][S:12][C:20]=12
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: Oc1ccnc2ccsc12
Agent: CCCCP(CCCC)CCCC
Product: ClCC[C@H](Oc1ccnc2ccsc12)c1ccccc1
Yield: 54 %

Procedure:
using (R)-(+)-3-chloro-1-phenyl-1-propanol, thieno[3,2-b]pyridin-7-ol (commercially available from the Aldrich Chemical Company), PBu3, and ADPP gave the title compound (0.71 g, 54%); Mass spectrum (ion spray): m/z=304.06 (m+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].C[Al](C)C.[C:18]([O:22][C:23]([N:25]([CH3:48])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:38]([C:39](OCC)=[O:40])=[CH:37][C:36]([C:44]([F:47])([F:46])[F:45])=[N:35]2)[CH2:30][CH2:29]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:48][N:25]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:38]([C:39](=[O:40])[NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]([F:12])([F:13])[F:1])=[CH:37][C:36]([C:44]([F:45])([F:47])[F:46])=[N:35]2)[CH2:30][CH2:29]1)[C:23](=[O:24])[O:22][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(CCN1CCC(n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2OC(F)(F)F)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-(Trifluoromethoxy)benzylamine (58.6 mg, 0.307 mmol) in toluene (1.239 mL) at 0° C. was added trimethylaluminium (2M in toluene, 0.557 mL, 1.115 mmol) dropwise. The mixture was stirred for 5 min at 0° C., then a solution of 95 (125 mg, 0.279 mmol) in toluene (0.620 mL) was added dropwise. The mixture was stirred at room temperature for 1 h, then at 55° C. for 1 h, and at 95° C. for 1.5 h till the reaction was complete. Saturated NaHCO3 was added to the reaction mixture followed by extraction with EtOAc. The organic extracts were dried over MgSO4, filtrated and concentrated and the residue was purified via Biotage (5% to 20% MeOH/CH2Cl2; 12M column) to give 99 as yellow oil. LRMS (ESI): calc.593.6; found 594.3 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:18]([OH:29])=[CH:19][C:20]4[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=4[CH:28]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:18](=[CH:19][C:20]5[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=5[CH:28]=4)[O:29][CH2:37]3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN1C(=O)COc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′ (1′H,3H)-dione was obtained (32%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.23 (m, 11H), 7.19-7.10 (m, 1H), 7.07-6.98 (m, 1H), 6.88 (s, 1H), 6.72 (s, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.20 (s, 1H), 4.93 (d, J=9.4 Hz, 1H), 4.82 (d, J=9.4 Hz, 1H), 4.57 (s, 2H), 3.01 (s, 3H); MS (ES+) m/z 489.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:24][CH2:23][CH3:25])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(Cl)c21
Yield: 61.1 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 2-iodopropane (0.07 mL, 0.7 mmol) to give the title compound (0.100 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1([CH3:19])[C:8]([CH3:10])(Br)[CH:7]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:19])[CH:8]([CH3:10])[CH:7]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(C=Cc2ccccc2)C1(C)Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1C(C=Cc2ccccc2)OC(=O)CC1(C)O
Yield: 48.5 %

Procedure:
The product obtained by reducing 680 mg of 3-hydroxy-3,4-dimethyl-4-bromo-7-phenyl-6-hepten-5-olide with 6.0 g of tri-n-butyltin hydride in 10 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was purified by a thin layer chromatography affording 250 mg of the desired compound as an oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:17])=[N:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:5]1.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)#[N:19]>CO>[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:17])=[N:11][CH2:12][C:13]([F:14])([F:16])[F:15])=[N:5]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCO)n1
Solvent: CO
Product: N#Cc1ccc(COCCn2ccc(NC(N)=NCC(F)(F)F)n2)cc1
Yield: 55 %

Procedure:
A mixture of 1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (2.5 g.) and 4-cyanobenzyl bromide (1.96 g.) was heated at 140° for 10 minutes. When cool, the residue was dissolved in a little MeOH and purified by medium pressure chromatography on silica gel using triethylamine/EtOH/EtOAc 1:10:95 v/v/v as eluant to give 1-[2-(4-cyanobenzyloxy)ethyl]-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (yield 55%) having the following n.m.r. spectrum in d6DMSO: 7.5 (br m, 5H); 5.85 (d, 1H); 5.1 (s, 2H); 4.05 (br m, 4H); 3.7 (br t, 2H).
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.O.Cl[CH2:26]Cl>CO>[OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH3:26])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCl
Reactant: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 3-(4-hydroxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionic acid (3.85 g) in dry methanol (60 ml) was added conc. sulfuric acid (3.8 ml) in one portion at 5° C. After stirring for 3 hours at ° C., the mixture was poured into a mixture of water (100 ml) and dichloromethane (50 ml). The aqueous layer was extracted with dichloromethane (50 ml) once again. The combined organic layers were washed with water three times, dried, and evaporated to dryness. To the residue was added diethyl ether and the solid was collected by filtration to yield methyl 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (3.49 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C(OOC(C)(C)C)(C)(C)C>O.C(O)(=O)C>[C:10]([C:5]1[N:4]=[CH:3][C:2]([C:7]([OH:9])=[O:8])=[N:1][CH:6]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)c1cnccn1
Agent: CC(C)(C)OOC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc(C(=O)c2ccccc2)cn1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a stirred, cooled (0° C.) solution of 2-pyrazine carboxylic acid (3.0 g, 24.2 mmol) and benzaldehyde (7.4 mL; 73 mmol) in a 50% aqueous solution of sulfuric acid (40 mL) and 25 mL of acetic acid was added FeSO4 7 H2O (20.3 g, 73 mmol dissolved in 50 mL of water) and t-butyl peroxide (9.2 mL; 73 mmol) simultaneously. After stirring for 1 hour, the reaction was treated with 200 mL of water. A precipitate formed which was filtered and washed with methylene chloride (3×100 mL) to yield a tan solid (36% yield).
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH2:3][CH2:2]1.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:20]([N:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH2:3][CH2:2]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)CCc1cnn2c1NCC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: NC(=O)CCc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Temperature: 60 °C
Reaction time: 17 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanamide (6 g) in pyridine (60 ml) was added triphenylmethyl chloride (11.1 g) at room temperature. The mixture was stirred at 60° C. for 17 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 3-(1-trityl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanamide (11.2 g).