Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=C(C=C[CH:10]=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39]CCCC1>>[C:3]([C:55]1[CH:54]=[CH:53][C:52]([CH2:40][CH2:34][CH2:39][N:24]2[CH2:25][C@@H:26]3[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]3[CH2:23]2)=[CH:57][CH:56]=1)([CH3:4])([CH3:10])[CH3:2]
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCc3ccc(C(C)(C)C)cc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-(4-tert-butylphenyl)propanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57 (t, J=8.5, 1H), 7.65 (t, J=6.6, 2H), 7.40 (dd, J=5.4, 8.0, 2H), 7.34 (t, J=7.4, 2H), 7.30-7.23 (m, 3H), 4.37 (dt, J=6.1, 11.1, 1H), 3.23 (d, J=10.4, 1H), 2.96 (dd, J=1.9, 8.9, 0.5H), 2.67 (ddd, J=6.7, 11.6, 23.3, 2H), 2.59 (dd, J=2.6, 9.3, 0.5H), 2.57-2.51 (m, 0.5H), 2.50-2.44 (m, 0.5H), 2.43-2.38 (m, 0.5H), 2.35 (t, J=8.1, 2H), 2.29 (dd, J=2.6, 8.8, 0.5H), 2.25 (t, J=7.1, 1H), 2.19 (d, J=7.2, 0.5H), 2.17-2.11 (m, 1H), 1.92-1.85 (m, 1H), 1.81 (dt, J=7.7, 15.5, 1H), 1.74 (dt, J=7.9, 15.9, 1H), 1.69-1.63 (m, 0.5H), 1.46-1.31 (m, 2H), 1.28 (s, 9H), 1.23 (dd, J=6.5, 13.4, 3H), 0.94-0.84 (m, 2H), 0.71 (dd, J=3.2, 6.6, 3H); MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: [CH3:1][OH:2].[CH3:3][O:4][C:5](=[O:8])[CH:6]=[CH2:7].[Br-:9].[K+]>O>[Br:9][CH:6]([CH2:7][O:2][CH3:1])[C:5]([O:4][CH3:3])=[O:8]
Reactant: C=CC(=O)OC
Reactant: CO
Reactant: [Br-]
Agent: [K+]
Solvent: O
Product: COCC(Br)C(=O)OC
Reaction time: 72 h

Procedure:
To a solution of 45 g. of methanol (dried over magnesium) and 33.7 g. of methylacrylate was added 120 g. of mercuric acetate. The mixture was allowed to stand at room temperature for three days with occasional shaking (after this period a small amount of unreacted mercuric acetate remained). The reaction mixture was cooled in an ice-bath and a solution of 45 g. of potassium bromide in 150 ml. of water was added, dropwise with strirring, during 25 mins. The heavy white oil which separated was extracted with 20 ml. of chloroform and the aqueous layer extracted with two further 50 ml. portions of chloroform. The combined chloroform extracts were washed with four 60 ml. portions of distilled water, dried and filtered. The filtrate in a 600 ml. beaker was exposed to two No. 2 photoflood lamps which were mounted in suitable reflectors as near the surface of the solution as possible and maintained at 50° to 57°C whilst 56.3 g. of bromine was added, with stirring, at such a rate as to keep up with its consumption. When all the bromine had been consumed, the reaction mixture as cooled for 15 mins. in an ice-bath and the precipitated mercuric bromide was removed by filtration and washed carefully with chloroform. The filtrate was concentrated under reduced pressure to yield an oil. Infra-red and proton NMR spectroscopy confirmed the desired product was obtained. The product, Methyl α-bromo-β-methoxy propionate (68.9 g., 100% yield based on bromine) showed a single peak by gas-liquid chromatography. It was desirable to freshly distil the product before use in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Br[CH:13]([CH3:17])[C:14](=O)[CH3:15].C(#N)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:13]([CH3:17])=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:6]([C:7]([NH2:9])=[O:8])[CH:10]=1
Reactant: CC(=O)C(C)Br
Reactant: NC(=O)c1cnc(N)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
5,6-Diaminonicotinamide (12.5 g, 82 mmol), 3-bromo-2-butanon (13.6, 90 mmol) and acetonitrile (150 ml) were refluxed for 20 h. Additional 3-bromo-2-butanon (4.0 g, 26.5 mmol) was added and the reaction mixture was refluxed for 5 h. Upon cooling the solids were removed by filtration. The solids were added to methylene chloride (150 ml), methanol (150 ml) and potassium carbonate (22 g, 160 mmol) and were stirred for 30 min. The solids were removed by filtration and evaporation of the solvents under reduced pressure gave an oily residue. Purification by column chromatography on silica gel eluting with methylene chloride:methanol (5:1) gave 3.3 g (20%) of the title compound.
Reaction SMILES: C1(S[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][C@H:18]4[CH2:22][O:21][C:20](=[O:23])[NH:19]4)[CH:15]=3)[NH:10][CH:9]=2)C=CC=CC=1>[Ni].CC(O)C>[O:23]=[C:20]1[NH:19][C@@H:18]([CH2:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[CH:8]3)[CH2:22][O:21]1
Reactant: O=C1N[C@@H](Cc2ccc3[nH]cc(Sc4ccccc4)c3c2)CO1
Agent: [Ni]
Solvent: CC(C)O
Product: O=C1N[C@@H](Cc2ccc3[nH]ccc3c2)CO1
Reaction time: 2 h

Procedure:
Raney nickel (3.0 g) was added to a solution of the product from step (a) (3.1 g) in IPA (150 ml) and the suspension refluxed for 1 hour. More Raney nickel (2.0 g) was added and refluxing continued for a further 2 hours. The suspension was filtered hot through Hyflo and the filtrate evaporated in vacuo to give an oil. The latter was eluted through a silica column using ethyl acetate as eluant to give the desired product as a froth (1.3 g). 1H NMR and MS were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]2[C:14]3[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:15]=3[S:16][C:7]=12.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:21][C:19]1[CH:18]=[CH:17][C:15]2[S:16][C:7]3[C:8](=[N:9][CH:10]=[C:11]([C:12]#[N:13])[C:6]=3[NH:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=3)[C:14]=2[CH:20]=1
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Nc1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2c(sc3ccc(N)cc32)c1Nc1cccc(Br)c1
Yield: 21.4 %

Procedure:
A mixture of 436 mg (1.03 mmol) of 4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile, 291 mg (5.19 mmol) of iron powder and 416 mg (7.77 mmol) of ammonium chloride in 160 mL of methanol and 110 mL of water is heated at reflux for 5.5 hours. The reaction mixture is filtered hot and the solid residue is extracted with several portions of hot ethyl acetate followed by hot methanol. All the organic layers are combined and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether and hexane are added and the solid is collected by filtration to provide 87 mg of 8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile. The filtrate is concentrated and purified by flash chromatography, eluting with a gradient of 1:1 hexane/ethyl acetate to 100% ethyl acetate to give an additional 56 mg of 8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile as a bright yellow solid, mp 295-300° C. dec.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][CH:6]([OH:12])[CH2:5]1.I[CH3:15]>C1(C)C=CC=CC=1>[CH3:15][O:12][CH:6]1[CH2:7][CH2:8][C:9]([CH3:11])=[CH:10][C:4]([CH3:13])([CH3:3])[CH2:5]1
Reactant: CC1=CC(C)(C)CC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC1CCC(C)=CC(C)(C)C1
Temperature: 98 °C

Procedure:
Sodium hydride (60% in mineral oil) (5.4 gm) was added to 60 gm toluene in a stirred reaction flask and stirred under nitrogen. 3,3,5-Trimethyl-4-cyclohepten-1-ol (15.4 gm) was then added over 10 minutes at room temperature and stirred overnight. Iodomethane (21.3 gm) was added dropwise over 10 minutes followed by heating at 45° C. for six hours and four hours at 98° C. The reaction mixture was washed with 50 mL of saturated sodium bicarbonate solution and distilled through a short Vigreux column. A heart cut fraction, 3,3,5-trimethyl-4-cyclohepten-1-yl methyl ether, was obtained that weighed 13.9 gm and had a boiling point of 85° C. at 10 mm pressure. Its GC purity was 97%. The fraction was evaluated for its odor quality and characterized as fresh, spicy, saffron-like, floral, (marigold)-herbaceous-woody-powerful.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1.[CH3:11][N:12]=[C:13]=[S:14]>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:13](=[S:14])[NH:12][CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: CN=C=S
Reactant: Nc1nc2c(s1)CNCC2
Solvent: CN(C)C=O
Product: CNC(=S)N1CCc2nc(N)sc2C1
Yield: 54.7 %

Procedure:
1.55 G (10 mmol) of 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine was dissolved in 25 ml of dimethylformamide and the solution was cooled in an ice-water bath. 0.88 g (12 mmol) of methyl isothiocyanate was then added. After 71/2 hours the solvent was removed by evaporation and the residue (about 2.2 g) was crystallized from acetonitrile. 1.25 g (55% yield) of the pure title compound (m.p. 188°-190° C. with decomposition) were obtained.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:17][C:18]([OH:20])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.Cl.[CH3:40][C@H:41]1[NH:47][CH2:46][CH2:45][CH2:44][NH:43][C:42]1=[O:48]>ClCCl.CN(C=O)C>[C:8]([O:12][C:13]([NH:15][C@H:16]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:17][C:18]([N:47]1[CH2:46][CH2:45][CH2:44][NH:43][C:42](=[O:48])[C@H:41]1[CH3:40])=[O:20])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C[C@H]1NCCCNC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1C(=O)NCCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 28 h

Procedure:
To a solution of N-methylmorpholine (0.38 μL) and (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (1.0 g) in 20 mL of dichloromethane at −20° C. was added isobutyl chloroformate (0.39 mL). The resultant mixture was stirred for 1 h. (3R)-hexahydro-3-methyl-2H-1,4-diazepin-2-one hydrochloride (500 mg) and N-methylmorpholine (0.40 mL) in dichloromethane (5 mL) and DMF (8 mL) were added. The mixture was stirred for 28 h, initially at −20° C. and then with slow warming to ambient temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted sequentially with dichloromethane and ethyl acetate. The combined organic layer was washed sequentially with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (silica gel, 3 to 7% 10:1 methanol/concentrated ammonium hydroxide in dichloromethane) to afford the coupled product. This was further purified by dissolving the product in a mixture of ethanol (7.5 mL) and hexane (16 mL) at 50° C. The solution was allowed to cool to ambient temperature overnight, and then placed in the refrigerator for 3 h. The solid was collected and washed with cold 5% ethanol/hexane to give the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:17])[CH:9]([C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1)[OH:10].CCOCC>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[CH3:7][CH:8]([CH3:17])[C:9]([C:11]1[CH:16]=[N:15][CH:14]=[N:13][CH:12]=1)=[O:10]
Reactant: CC(C)C(O)c1cncnc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)c1cncnc1
Reaction time: 5 h
Yield: 48 %

Procedure:
To a suspension of chromium (VI) oxide (12.87 g, 65 mmol) in dry dichloromethane (500 ml) was added dry pyridine (10.27 g, 130 mmol) and the mixture stirred for 0 5 h. Then a solution of 2-methyl-1-(pyrimid-5-yl)-propan-1-ol, prepared in stage 1, (1.52 g, 10 mmol) in dry dichloromethane (100 ml) was added dropwise with stirring. After 2 hours the reaction mixture was poured into ether (1000 ml) and then filtered. The filtrate was washed with copper sulphate solution (4×400 ml), brine solution (2×400 ml), and dried over magnesium sulphate before removing the solvent. Flash chromatography (silica gel, petrol/ether elution) gave the product as a colourless oil (0.72 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)(=O)C.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(O)C>[CH3:21][N:22]1[CH2:27][CH2:26][C:25]2([C:16]3=[C:15]4[C:10](=[N:9][C:8]3=[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]3)[NH:1]2)[CH:11]=[CH:12][CH:13]=[CH:14]4)[CH2:24][CH2:23]1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: CN1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12
Yield: 35.6 %

Procedure:
To a solution prepared from 8 g of 2-(2-aminophenyl)indole, 2.5 ml of acetic acid and 100 ml of ethanol was added 5.15 g of 1-methyl-4-piperidone. The mixture was refluxed for 6 hours. Concentration gave a gum which was triturated with dilute NH4OH and the resultant solid was collected. Flash chromatography using 10% CH3OH/CH2Cl2 as an eluent gave 4.15 g of yellow solid, m.p. 228°-230° dec.
Reaction SMILES: N1CCCC1.[CH3:6][CH2:7][C:8](=O)[CH2:9][CH3:10].[OH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>CO>[CH2:7]([C:8]1([CH2:9][CH3:10])[CH2:21][C:20](=[O:22])[C:14]2[C:13](=[CH:18][C:17]([OH:19])=[CH:16][CH:15]=2)[O:12]1)[CH3:6]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCC(=O)CC
Solvent: C1CCNC1
Solvent: CO
Product: CCC1(CC)CC(=O)c2ccc(O)cc2O1
Reaction time: 24 h
Yield: 39.5 %

Procedure:
Pyrrolidine (9.3 g) and pentan-3-one (11.3 g) were added to a solution of 1-(2,4-dihydroxyphenyl)ethanone (14 g) in methanol (150 mL) and the solution was stirred for 24 hours and then heated under reflux for 10 hours. The reaction mixture was concentrated in vacuo, and to the residue was added water (10 mL). To the mixture was added 1N hydrochloric acid solution to adjust its pH to 5 to 6, and extracted with ethyl acetate (25 mL×3). The combined organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=10/1) to give the titled compound (8 g) as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([C@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:3])N.[CH2:35]([N:37](CC)CC)[CH3:36].C(Cl)(=[O:44])C.O>ClCCl>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH:1]=[N:3][NH:37][C:35](=[O:44])[CH3:36])[CH:12]=2)[CH:8]=[C:9]1[CH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])[CH3:14]
Reactant: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C=NNC(C)=O)cc2n1CC
Temperature: -78 °C
Reaction time: 3 h

Procedure:
52 mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-1-ethylindol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate obtained in Example 60 was dissolved in dry dichloromethane. To the resulting solution was added 31 μl of triethylamine, and the mixture was cooled to −78° C. After 16 μl of acetyl chloride was added, the reaction solution was stirred for 3 hours and warmed to room temperature. Water was added and the mixture was extracted with dichloromethane. The extract was dried over MgSO4 and evaporated under reduced pressure to remove the solvent. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/methanol(50:1)] to obtain 7 mg of the title compound as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[NH:13]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1C=CC=CC=1.[OH-].[Na+].C(O)C>[C:1]([O:26][C:23]1[CH:22]=[CH:21][C:20]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1)Oc1ccc(Nc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
4-Anilinophenyl cinnamate was prepared by adding a solution of 18.2 grams of cinnamoyl chloride in 50 milliliters of benzene to a solution of the sodium salt of 4-anilinophenol which was prepared by dissolving 18.5 grams of 4-anilinophenol in a solution of 4 grams of sodium hydroxide in 100 milliliters of ethanol. The addition was accomplished in 30 minutes and the reaction mixture was stirred for one hour. The mixture was then poured into 150 milliliters of water. The organic layer was separated, washed three times with 10 percent sodium hydroxide solution and once with water, dried over anhydrous sodium sulfate, then allowed to evaporate. The residue was washed with boiling hexane. There was obtained 15.0 grams of product which melted at 116°-118° C.
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([CH3:8])N=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].S1C=CC=[C:33]1C1C=CC=CC=1C(O)=O>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:22]([C:23]([N:14]2[CH2:13][CH2:12][C@@H:11]3[C@@H:16]([N:9]([C:4]4[CH:8]=[CH:6][C:7]([CH3:33])=[CH:2][N:3]=4)[CH2:10]3)[CH2:15]2)=[O:24])[CH:26]=1
Reactant: O=C(O)c1ccccc1-c1cccs1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Product: Cc1ccc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc1

Procedure:
The title compound was prepared in a manner analogous to Example 1 substituting Intermediate 42 for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-thiophene-2-yl-benzoic acid. MS (ESI) mass calcd. for C21H21FN6O, 392.4; m/z found, 393.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[O:17][C:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methanol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1>CO.Cl>[ClH:27].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amine E5 (304 mg, 0.82 mmol) in dry MeOH (30 mL) were sequentially added 4-chloro-6-nitroquinoline (F1) (171 mg, 0.82 mmol) and c.HCl (1-2 drops), and the resulting mixture was refluxed for ˜12 h. MS and TLC analysis after this time showed some F1 was still present in the reaction mixture, so further aliquots of E5 (171 mg, 0.82 mmol) and c.HCl (1-2 drops) were added at 12 h and 24 h. Solvent was then removed from the reaction mixture, and the resulting residue dissolved in MeOH, and then re-concentrated under reduced pressure. The residue was subjected to a further MeOH azeotrope cycle, and the resulting residue was then reprecipitated from MeOH:Et2O to afford Cpd. H as an amorphous yellow solid (383 mg, 86%). 1H NMR (400 MHz, DMSO): 2.28 [s, 3H, ArCH3], 6.18 [brs, 1H, ArH], 7.11 [d, J=6.59 Hz, 1H, ArH], 7.65 Hz [d, J=8.52 Hz, 2H, ArH], 7.81 [m, 5H, ArH &ArNH2], 8.17 [d, J=8.52 Hz, 2H, ArH], 8.25 [d, J=9.30 Hz, 1H, ArH], 8.69 [m, 2H, ArH], 9.77 [s, 1H, ArH], 10.42 [s, 1H, ArH], 10.62 [br s, 1H, ArNHAr], 11.20 [v br s, 1H, ArNHAr], 12.63 [v br s, 1H, ArC(O)NH]. LCMS (APCl+): 508 (100%). HPLC: 98.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol) in dichloromethane (25 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.066 g, 0.57 mmol). After 2 hours, extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.42 (silica gel, 6% methanol/dichloromethane); mp; 64.0-66.0° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[CH3:14][O:13][C:11]1[CH:10]=[N:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=1
Reactant: Oc1cnn(Cc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-4-ol (Intermediate 4) (3.5 g, 20.1 mmol) and Cs2CO3 (8 g, 24.6 mmol) in DMF (100 mL) was added MeI (2 mL, 32 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc, washed with ice/brine. The aqueous was extracted with EtOAc, the combined organic solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 60:40 as eluant) to give the title compound 4-(methyloxy)-1-(phenylmethyl)-1H-pyrazole (2.5 g, 13.3 mmol, 63% yield) as a yellow oil. LCMS: (M+H)+=189; Rt=0.81 min.