Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])[CH:38]=[CH:39][CH:40]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42](=[O:43])[NH:44][CH:45]3[CH2:47][CH2:46]3)[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(Cc1cccc(Br)c1)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1)NC1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 2-(3-bromo-phenyl)-N-cyclopropyl-acetamide (42.0 mg, 0.17 mmol), and Pd[P(Ph)3]4 (14.3 mg, 7.5 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.3 mg. MS: 498.2 (M+H+); H1 -NMR (DMSO-d6): δ (ppm) 0.31-0.39 (m, 2H), 0.52-0.60 (m, 2H), 1.74-2.00 (m, 3H), 2.10-2.30 (m, 1H), 2.50-2.62 (m, 1H), 3.34-3.54 (m, 2H), 4.28-4.38 (m, 1H), 4.85-5.08 (m, 2H), 6.95-7.55 (m, 12H), 7.80-7.92 (m, 1H), 8.05-8.18 (m, 1H), 10.05-10.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:43]([N:50]1[CH2:55][CH2:54][O:53][CH:52]([C:56]2[CH:61]=[CH:60][C:59]([CH2:62]O)=[CH:58][CH:57]=2)[CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH2:43]([N:50]1[CH2:55][CH2:54][O:53][CH:52]([C:56]2[CH:57]=[CH:58][C:59]([CH2:62][O:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[CH:60][CH:61]=2)[CH2:51]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: OCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Oc1c(Cl)cccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1OCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144 %

Procedure:
To a solution of 2,6-dichlorophenol (0.68 g; 4.19 mmol) in THF (20 mL) was added DIAD (1.13 mL; 5.72 mmol), and triphenylphosphine (1.50 g; 5.72 mmol), at RT, followed, after 30 minutes, by [4-(4-benzyl-morpholin-2-yl)-phenyl]-methanol (1.08 g; 3.81 mmol). Subsequently, the resulting mixture was stirred at RT for 1 hour, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine (2.35 g) which was used as such in the next step.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21]OS(C)(=O)=O)[N:19]=2)=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]3[CH3:1])[N:19]=2)=[CH:13][CH:14]=1
Reactant: CC1CCCCN1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1C
Yield: 100.6 %

Procedure:
Add 2-methylpiperidine (3.55 g, 36.1 mmol) to a solution of Methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (See Intermediate 13) (1.3 g, 3.61 mmol) in anhydrous THF (15 mL). Reflux the reaction overnight and cool. Wash organic material with 1N HCl (50 mL) and extract aqueous layer with diethyl ether (2×50 mL). Add 5N NaOH to aqueous layer (pH>10) and extract with dichoromethane (2×50 mL). Dry organics over Na2SO4, filter and concentrate to give 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-methylpiperidine (1.32 g, quant).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:28])([F:27])[CH2:15][CH:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17].[I:29]I>O1CCCC1>[F:28][C:14]([F:13])([F:27])[CH2:15][C:16]([I:29])([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: II
Reactant: CC(CC(F)(F)F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(I)(CC(F)(F)F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of 28.5 mmol diisopropylamine in 18 ml tetrahydrofuran at −78° C. was added dropwise 28.5 mmol n-butyllithium solution (1.6 M in hexane) and the mixture was then warmed to room temperature. The resulting solution was then added dropwise over 50 min to a solution of 19.0 mmol rac-(4,4,4-trifluoro-butane-2-sulfonyl)-benzene in 30 ml tetrahydrofuran at −78° C. and stirring continued for a further 15 min at −78° C. Finally, a solution of 20.9 mol iodine in 15 ml tetrahydrofuran was added dropwise over 15 min and stirring continued for a further 15 min at −78° C. and then the reaction mixture was allowed to warm to −20° C. The reaction mixture was quenched by addition of 1 M hydrochloric acid and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed sequentially with aqueous sodium thiosulfite solution and with brine and then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a yellow oil (yield 87%). EI-MS (m/e): 377.9 (M+, 4%), 237.0 ([M−PhSO2]+, 40%), 142.0 (PhSO2H+, 100%), 125.1 (PhSO+, 93%), 78.2 (PhH+, 40%), 77.2 (Ph+, 31%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1>>[C:25]1([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)Cc1ccccc1-c1ccccn1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(Cc1ccccc1-c1ccccn1)N[C@H]1CCN(CCc2ccccc2)C1

Procedure:
2-(2-pyridyl)phenylacetic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-2-(2-pyridyl)phenylacetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][N:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][N:9]([C:10]1[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)[CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Yield: 87.9 %

Procedure:
A mixture of 1.6 g (0.0045 mole) of 3-[butyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-propionic acid tert-butyl ester (IV-44) in 50 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 1.3 g of 3-[(5-amino-2-chloro-pyrimidin-4-yl)-butyl-amino]-propanoic acid tert-butyl ester (V-44). This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.86 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 87 to 89/9 to 13. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.86 to 0.88%].
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH:24]=1>>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][CH:13]=2)[CH:7]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([N:23]3[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]3)[CH:26]=2)[N:3]=1
Reactant: Cc1cn(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Product: Cc1cn(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)c2)cn1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (400 mg, 1.09 mmol) and 4-methyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole [in situ prepared by the following sequence:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:36])([CH2:32][CH2:33][CH:34]=C)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]=[O+][O-]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:36][CH:34]([OH:37])[CH2:33][CH2:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCC(O)(CCOCCCCCCCCCCCCCCCCCC)COCc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(O)O1
Temperature: 25 °C

Procedure:
6.15 g (12.3 mmol) of the compound prepared in (c) above in 100 ml of methylene chloride was treated with ozone at -60° C. After consumption of the olefin, 25 ml of dimethyl sulfide was added and the mixture allowed to warm to room temperature. The solvent was removed in vacuo and the crude product was purified on silica gel employing a mixture of petroleum ether and diethylether in a ratio of 7:3 as the eluent to yield a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[CH3:26][N:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)N>>[CH3:26][N:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:19]=[C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]3[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=3)[CH:10]=2)[NH:14][C:13]1=[O:18]
Reactant: CN(N)c1ccccc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NN(C)c1ccccc1)C(=O)N2
Yield: 47 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 1-methyl 1-phenylhydrazine and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:8](CC3C=CC(OC)=CC=3)[N:7]=[C:6]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH3:32])=[CH:20][N:19]=3)[C:5]=2[CH3:33])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>ClCCCl>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH3:32])=[CH:20][N:19]=3)[C:5]=2[CH3:33])[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c(C)c2C2CC2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
880 mg of 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2.0 mmol, 1.00 eq.) were dissolved in 7.8 mL of dry 1,2-dichloroethane. 4.6 mL trifluoroacetic acid (60 mmol, 30 eq.) and 1.8 mL trifluoromethanesulfonic acid (20 mmol, 10 eq.) were added at rt. The reaction mixture was stirred at 75° C. for 2 h. At 0° C. 2M sodiumhydroxide solution was added slowly. The solid was filtered off, dried in vacuo at 50° C. to provide 637 mg (1.96 mmol, 98%) of the analytically pure target compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14]2)=[C:6]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:5]=1.[CH3:38][C:39]([CH3:41])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:6]2[N:5]=[C:4]([CH2:3][CH2:2][NH:1][CH:39]([CH3:41])[CH3:38])[N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)=O
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC(C)C)nc32)[C@H](O)[C@@H]1O
Yield: 41.9 %

Procedure:
The title compound was prepared by a similar method to example 12 using (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 11) (120 mg, 0.24 mmol), acetone (14 mg, 0.24 mmol), acetic acid (16 mg, 0.27 mmol) and sodium triacetoxyborohydride (75 mg, 0.35 mmol) to afford the title compound as a solid (55 mg). MS: 547 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[CH3:24][N:25]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](N1C=C[N+](C)=C1)=[O:27]>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:26](=[O:27])[N:25]([CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:9]=2
Reactant: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(O)ccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-(2,6-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=468 (M+1), Rt: 5.37 min.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:17])[CH:6]2[O:15][CH3:16].[Li]CCCC.[CH2:23]1[O:25][CH2:24]1.O>C1COCC1>[C:11]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH:5]([CH3:17])[CH:6]2[O:15][CH3:16])=[C:2]([CH2:23][CH2:24][OH:25])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC1c2cc(C(C)(C)C)cc(Br)c2CC1C
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC1c2cc(C(C)(C)C)cc(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 40.0 g (134.5 mmol) of 4-bromo-6-tert-butyl-1-methoxy-2-methylindane in 250 ml of THF 107.7 ml of 2.5 M (269 mmol) n-BuLi in hexanes was added for 20 min at −80° C. This mixture was stirred for 40 min at this temperature, cooled to −110° C., and 11.85 g (269.15 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 h at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 200 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using short column with Silica Gel 60 (40-63 um, d 110 mm, l 90 mm; eluent: hexanes/ether=20/1). Yield 27.58 g (78%) of a ca. 1 to 2 mixture of two diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reaction time: 15 h
Yield: 98 %

Procedure:
To a mixture of 5-fluoro-2-nitrophenol (50.0 g), potassium carbonate (44.0 g) and N,N-dimethylformamide (150 mL) was added benzyl bromide (59.9 g) under ice-cooling, and the mixture was stirred for 15 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (77.1 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Reactant: Nc1cccc(F)c1
Product: Cc1cn(C)c2c(Nc3cccc(F)c3)ncc(C(=O)N3CCOCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and using 3-fluoroaniline (130 ul) instead of 3-bromoaniline and heating for 15 rather than 30 minutes to give 1-[7-(3-fluoro-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (89 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[C:8]2[C:12](=[O:14])[CH3:13])=[CH:15][CH:16]=1
Reactant: CC(=O)c1cccn1Cc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])cn1Cc1ccc(F)cc1
Temperature: -78 °C

Procedure:
To a 500 mL round bottomed flask with a stirring bar and a drying tube was added 1-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AI-1-1 (11.64 g, 53.58 mmol) and acetic anhydride (230 mL). This solution was cooled to −78° C. and concentrated nitric acid (3.7 mL of 15.9 N solution, 58.24 mmol) was added with a pipette. The cooling bath was allowed to expire and the mixture warmed to 0° C. over 7 h. The acetic anhydride was removed in vacuo and the residue was taken up in EtOAc (500 mL). This solution was washed with saturated aqueous NaHCO3 solution (2×) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 20% EtOAc in hexane as eluant. An impure yellow crystalline solid was obtained. This material was recrystallized from Et2O/hexane to give white crystals of 1-[1-(4-fluorobenzyl)-4-nitro-1H-pyrrol-2-yl]ethanone AVI-1-1. 1H NMR (CDCl3) δ 2.55 (3H, s), 5.54 (2H, s), 7.06 (2H, m), 7.20 (2H, m), 7.47 (1H, d, j=1.8 Hz), 7.63 (1H, d, j=1.8 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][CH2:10][C:11](Br)=[O:12].CCN(CC)CC>C(Cl)Cl>[Br:9][CH2:10][C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)=[O:12]
Reactant: Nc1cccc(I)c1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of 3-iodoaniline (2.19 g, 10.0 mmol) and 2-bromoacetyl bromide (0.87 mL, 3.40 g, 10.0 mmol) in DCM (100 mL) was added Et3N (1.39 mL) at 0° C. The reaction mixtures were stirred at room temperature for overnight. The reaction mixtures were diluted with DCM (100 mL), washed with water, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 10% EtOC in hexanes to 100% EtOAc to afford 2-bromo-N-(3-iodophenyl)acetamide (2.824 g, 83%). MS (ESI), 340, 342 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:20].[K+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([NH2:18])=[O:20])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([CH3:19])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: Cn1nc(C(C)(C)C)cc1Nc1cccnc1C#N
Agent: [K+]
Solvent: CO
Product: Cn1nc(C(C)(C)C)cc1Nc1cccnc1C(N)=O
Temperature: 40 °C
Reaction time: 48 h
Yield: 6 %

Procedure:
To a solution of 3-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]pyridine-2-carbonitrile (100 mg, 0.39 mmol) in MeOH (1 mL) was added an aqueous solution of KOH (3 M, 1 mL), and the mixture was stirred at 40° C. for 48 h. The organic solvent was removed under reduced pressure, and the aqueous layer was acidified to pH 1 to 2 with 1 N aqueous HCl. The mixture was extracted with ethyl acetate (3×). After removal of the solvent under reduced pressure, the crude residue was subjected to preparative HPLC purification with a gradient elution from 20% to 90% acetonitrile in water to give the above product as an oil (6.2 mg, 6%). 1H NMR (400 MHz, CD3OD) δ 1.35 (s, 9H), 3.72 (s, 3H), 6.80 (s, 1H), 7.39-7.42 (m, 2H), 8.08-8.11 (m, 1H). ES-MS m/z 274.1 (MH+), HPLC RT (min) 1.47.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:15])(=O)=O>ClCCl>[Cl:15][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1cc(OC2CCCC2)cs1
Solvent: ClCCl
Product: Clc1sccc1OC1CCCC1
Reaction time: 1 h
Yield: 57.2 %

Procedure:
2-Chloro-3-cyclopentyloxythiophene was prepared according to the procedures described in P. Stanetty and E. Puschautz, Monatshefte Chemie, 1989, 120, 65. Thus, to a solution of 3-cyclopentyloxythiophene (3.98 g, 23.7 mmol) in dichloromethane (35 mL) was added sulfuryl chloride (2 mL, 24.9 mmol) at 15° C. under argon. The mixture was stirred for 1 hour, then concentrated to dryness. Purification by flash chromatography (silica, 100% hexane) gave 2-chloro-3-cyclopentyloxythiophene (2.75 g, 59%) as a pale yellow oil; 1HNMR (300 MHz, CDCl3) δ 6.99 (d, J=6.0 Hz, 1H), 6.75 (d,J=6.0 Hz, 1H), 4.69-4.74 (m, 1H), 1.7-1.93 (m, 6H), 1.5-1.7 (m,2H). MS m/e (%): 202 (M+; 6).