Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>>[CH2:26]([N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:28])[CH:7]=1)[C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH3:27]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: CC(C)C(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C(C)C

Procedure:
{2′-[(Ethyl-isobutyryl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-246) was prepared using the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and isobutyryl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Mg].Cl[CH:11]1[CH2:15][CH2:14][CH:13]=[CH:12]1>O1CCCC1>[CH2:2]([CH:15]1[CH2:14][CH2:13][CH:12]=[CH:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClC1C=CCC1
Reactant: CCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCC1C=CCC1
Yield: 51.8 %

Procedure:
The procedure followed is the same as that described in Example 20 substituting 1-bromoheptane (100 g, 0.56 moles) diluted in tetrahydrofuran (100 ml), granular magnesium (25 g) in tetrahydrofuran (100 ml), 0.1 M solution of Li2CuCl4 (1.7 mmoles), and 3-chlorocyclopentene (57 g, 0.56 moles) diluted in tetrahydrofuran (200 ml). The crude product is fractionally distilled under vacuum leaving a clear, colorless oil (49 g, 0.29 moles), BP 41° C./0.35 mm.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH:5]([C:7]1[N:8]=[N:9][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([CH3:13])[N:12]=1)[NH2:6]>C(Cl)Cl.C(OC(C)C)(C)C>[CH3:13][C:11]1[N:12]=[C:7]([NH:5][NH:6][C:3]([NH:2][CH3:1])=[O:4])[N:8]=[N:9][C:10]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN=C=O
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CNC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Yield: 98.7 %

Procedure:
A solution of methyl isocyanate (0.92 g) in methylene chloride (3 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3 g) in methylene chloride (20 ml) at room temperature. The reaction mixture was diluted with diisopropyl ether (30 ml). The resultant precipitates were collected by filtration to give a solid of 5-methyl-3-(4-methylsemicarbazido)-6-phenyl-1,2,4-triazine (3.8 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:25][CH2:24]2)=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccc(F)cc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.050 g (0.112 mmol) of {3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone, hydrochloride salt was dissolved in 3 ml of DMF. 61.9 mg (0.448 mmol) of potassium carbonate was added to the solution, followed by 0.021 g (0.11 mmol) of 1-Bromomethyl-4-fluoro-benzene. The reaction solution was shaken for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with water and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), and DCM/MeOH (10/1).
Reaction SMILES: C1N2CCN(CC2)C1.[CH3:9][N:10]=[C:11]=[O:12].[CH3:13][NH:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>O1CCOCC1>[CH3:13][NH:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:11]([NH:10][CH3:9])=[O:12])[CH:18]=1
Reactant: CNC(=O)Cc1cccc(N)c1
Reactant: CN=C=O
Agent: C1CN2CCN1CC2
Solvent: C1COCCO1
Product: CNC(=O)Cc1cccc(NC(=O)NC)c1
Reaction time: 3 h

Procedure:
0.1 g of triethylenediamine, followed by 5.7 g (0.1 mol) of methyl isocyanate, was added to a solution of 16.4 g (0.1 mol) of 3-amino-phenylacetic acid methylamide in 100 ml of dioxane at room temperature. The mixture was stirred for a further 3 hours at 40° to 50° C. After cooling, the crystalline precipitate which had separated out was filtered off and dried. After recrystallization from ethanol, 19.5 g (88% of theory) of 3-(N'-methylureido)-phenylacetic acid methylamide of melting point 175°-177° C were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[N:10]=[CH:11][N:12]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccc(Oc2c[nH]cn2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
To a cold (0° C.) solution of 4-(4-bromophenyloxy) imidazole (1.2 g, 5.0 mmol) and triethylamine (0.76 mL, 5.5 mmol) in DMF (5 mL) under an atmosphere of argon, solid trityl chloride (1.46 g, 5.3 mmol) was added. The resultant mixture was stirred at room temp overnight. The product mixture was concentrated onto silica gel, loaded onto a column of silica gel, and eluted with a mixture of 9:1 chloroform and acetone. Collection and concentration of appropriate fractions provided the titled compound as white powder.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH:8]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>COCCOC>[C:21]([C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:18]=1[OH:25])[N:8]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Reactant: O=C1CCC(=O)O1
Solvent: COCCOC
Product: CC(C)(C)c1cc(N(C(=O)CCC(=O)O)c2ccccc2)cc(C(C)(C)C)c1O
Yield: 93.1 %

Procedure:
1.5 g (0.015 mole) of succinic anhydride, 4.5 g (0.010 mole) of 4-anilino-2,6-di-t-butylphenol, and 10 ml of 1,2-dimethoxyethane were combined and heated at reflux for 48 hours. 1.5 g of succinic anhydride and 5 ml of 1,2-dimethoxyethane were added and the reaction was heated for an additional 24 hours. The reaction mixture was cooled in an ice bath. The resulting precipitate was collected, rinsed with a small amount of cold 1,2-dimethoxyethane, and recrystallized from a mixture of ethanol and water to give 3.7 g of off-white 4-(3,5-di-t-butyl-4-hydroxy-N-phenylanilino)-4-oxobutanoic acid, m.p. 205°-208° C. Analysis: Calculated for C24H31NO4 : % C, 72.5; % H, 7.9; % N, 3.5: Found: % C, 72.4; % H, 7.8; % N, 3.3.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=3[F:36])[O:22][CH:23]=2)[CH:14]=[CH:13][C:3]=1[CH2:4][S:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[N:9]1.ClC1C=C(C(OO)=[O:45])C=CC=1>ClCCl.C(OCC)(=O)C>[F:36][C:27]1[CH:28]=[C:29]([C:32]([F:34])([F:33])[F:35])[CH:30]=[CH:31][C:26]=1/[CH:25]=[CH:24]/[C:21]1[O:22][CH:23]=[C:19]([CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:3]([CH2:4][S:5]([CH2:6][CH2:7][N:8]3[CH:12]=[CH:11][N:10]=[N:9]3)=[O:45])=[C:2]([CH3:1])[CH:16]=2)[N:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3F)n2)ccc1CSCCn1ccnn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3F)n2)ccc1CS(=O)CCn1ccnn1
Temperature: -30 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a solution of 650 mg (1.25 mmol) 1-[2-(2-methyl-4-{2-[2-(E)-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H[1,2,3]triazole in 35 ml dichloromethane at −30° C. were added dropwise during 20 min. 493 mg (2.20 mmol) 3-chloro-benzenecarboperoxoic acid (77% peracid) dissolved in 20 ml ethyl acetate. After 1 hour stirring at −30° C. the mixture was allowed to warm up over night, stirred another 48 hours at room temperature, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate (1–10% methanol gradient) furnished as the second fraction 310 mg (46%) title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[N:39]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[N:42]([CH3:43])[C:41]5[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=5[N:39]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 42 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-1-methyl-1H-benzimidazole.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])[CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[I:24]I>O1CCCC1>[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])[CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[I:24]
Reactant: II
Reactant: Cc1ccc(C)n1C(C)c1ncccc1F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A dry 250 ml 3-neck roundbottom flask equipped with a thermometer, rubber septum, magnetic stirrer, and nitrogen inlet was charged with 30 ml of anhydrous tetrahydrofuran and 2.1 ml (14.67 mmole) of dry diisopropylamine. The stirring solution was cooled to −78° C. After which 9.5 ml (15.11 mmole) of 1,6 n-butyllithium in hexanes was added over 10 minutes by syringe. The solution was stirred 30 minutes longer and 3.2 g (14.67 mmole) of N-[(3-Fluoropyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole in 30 ml of dry tetrahydrofuran was added dropwise via syringe over 30 minutes, keeping the internal temperature below −65° C. After stirring 30 minutes longer, a solution of 4.0 g (15.80 mmole) of iodine in 30 ml of dry tetrahydrofuran was added by canula over 10 minutes. The mixture was warmed to room temperature (a color change, quenching, occurred at −30° C.) and stirred overnight under nitrogen. The solution was diluted to 200 ml with ethyl ether, extracted with aqueous saturated sodium bicarbonate (IX), brine (IX), and dried over sodium sulfate. Filtration and concentration gave a dark solid which was purified by flash silica gel chromatography (20% ethyl acetate in hexanes) to give the titled compound as a white solid, 3,9 g (77%): mp 156-158° C.; IR (KBr, cm−1) 3000, 2950, 1574, 1408, 752; 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H) 7.85 (t, 1H), 5.60 (s, 2H), 4.05 (t, 2H), 3.00 (dt, 2H), 2.10 (s, 6H); MS (FD) m/e 344 (Mt). Anal. Calc'd. for C13H14FIN2: C, 45.37; H, 4.10; N, 8.14. Found: C, 45.07; H, 4.03; N, 8.06.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:36][C:34]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:35]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCN(CCN2CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 4.5 h
Yield: 81.6 %

Procedure:
After adding tetrahydrofuran (3 ml) and methanol (3 ml) to a crude product of 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (129 mg) under a nitrogen atmosphere, 10% palladium-carbon (60 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 4.5 hours. The atmosphere in the reaction vessel was then replaced with nitrogen, and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=19:1), and then Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of the title compound (98.4 mg) as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8].[N:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[C:18]=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[NH:17][C:18](=[O:19])[O:11][CH2:10][CH2:9][N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[Cl:1])=[O:12]
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: CN(CCO)C(=O)NCc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CN(CCOC(=O)Nc1ccc2ccccc2c1)C(=O)NCc1ccccc1Cl
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a solution of 3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (120 mg, 0.50 mmol) in THF (1.0 mL) were added DMAP (3.0 mg, 0.02) and 2-isocyanatonaphthalene (100 mg, 0.60 mmol). The reaction mixture was stirred for 30 min. LC/MS indicated the completion of the reaction. The mixture was filtered and the filtrate was purified by RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2-chlorobenzyl)-1-methylureido)ethyl naphthalen-2-ylcarbamate (165 mg, 80%). LRMS (M-Boc+H+) m/z 412.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:36])[CH:34]=[CH2:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH2:33][CH:34]=[CH2:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: C=CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C=CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 130 ml tetrahydrofuran was stirred at room temperature for 3 hours. Under a nitrogen atmosphere, N-allylamine (1.60 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to a solid, which was placed under high vacuum over the weekend. The solid residue was dissolved in isopropyl alcohol, filtered, and diluted with water to initiate crystallization, then refrigerated overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 3.0 g (66%) of title compound, mp 208°-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.O[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2=[N:8][N:9]([CH2:12][N:13]3[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]3=[O:21])[CH:10]=[C:4]2[CH:3]=1
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: Brc1cnc2[nH]ncc2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cn2cc3cc(Br)cnc3n2)C1
Yield: 7.8 %

Procedure:
A solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (1 g, 1 eq, 5.04 mmol) and 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (1.58 g, 2 eq, 10.08 mmol) in trifluoroacetic acid (20 ml) is refluxed for 4 hours. The reaction mixture is poured on crushed ice, on saturated NaHCO3 aqueous solution, and the aqueous phase is extracted with dichloromethane. The cumulated organic layers are dried over MgSO4, filtered, evaporated under reduced pressure. The crude product is purified by preparative chromatography on silicagel affording 1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one 291 as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11])(=[O:23])[CH2:21][CH3:22]
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1c2ccccc2CC1C(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of indoline-2-carboxilic acid (8.16 g, 50 mmol) and triethyl amine (10 mL, 71.74 mmol) in anhydrous CH2Cl2 (60 mL) containing catalytic amount of DMAP was added dropwise a solution of propionyl chloride (5.55 g, 60 mmol) in CH2Cl2 (20 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for 2.5 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The residue was crystallized from methanol to yield 1-propionyl-2,3-dihydro-1H-indole-2-carboxylic acid as a white solid, 9.19 g (83%): mp 173-175° C.; 1H NMR (DMSO-d6) δ1.05 (3H, t, J=7.6 Hz, Me), 2.51 (2H, d, J=7.6 Hz, CH2), 3.17 (1H, d, J=16.0 Hz, CH), 3.57 (1H, dd, J=11.0 Hz, J=16.0 Hz, N—CH), 5.15 (1H, d, J=16.0 Hz, CH), 6.98-7.01 (1H, m, ArH), 7.15-7.23 (2H, m, 2×ArH), 8.07-8.09 (1H, m, ArH), 13.26 (1H, brs, exchangeable, OH). Anal. Calcd. for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.73; H, 6.07; N, 6.34.
Reaction SMILES: [CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=C)[CH3:2].C[N+]1([O-])CC[O:27]CC1.O.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=[O:27])[CH3:2]
Reactant: C=CCC(CCOCc1ccccc1)O[Si](CC)(CC)CC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(CC=O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.0 g (31.2 mmol) of 4-Triethylsilyloxy-6-benzyloxy-1-hexene in 310 mL of tetrahydrofuran at 0°C. were added 4.38 g (37.4 mmol) of 4-methylmorpholine N-oxide, 6.24 mL (1.248 mmol) of osmium tetroxide (0.2M in benzene) and 45 mL of water and stirred overnight at room temperature. To the mixture at 0° C. were added 185 mL of water and 20.02 g (93.6 mmol) of sodium periodate and stirred at room temperature for 1 hour, followed by partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated for the next reaction. 1H NMR (CDCl3): δ 9.79 (t, J=2.4 Hz, 1H, CH═O), 7.35-7.31 (m, 5H, ArH), 4.51 (d, J=12.0 Hz, 1H, ArCH2O), 4.46 (d, J=12.0 Hz, 1H, ArCH2O), 4.40 (p, J=6.0 Hz, 1H, CH—O), 3.55 (m, 2H, CH2—O), 2.56 (m, 2H, CH2C═O), 1.85 (m, 2H, CH2), 0.94 (t, J=8.1 Hz, 9H, TES CH3), 0.59 (q, J=8.1 Hz, 6H, TES CH2). 13C NMR (CDCl3): δ 201.94, 138.14, 128.31, 127.60, 127.55, 72.99, 66.31, 65.49, 51.14, 37.71, 6.84, 4.88.
Reaction SMILES: [CH:1]1([CH2:7][C:8](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].N>>[C:11]([NH:15][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=C(O)CC1CCCCC1
Agent: N
Product: CC(C)(C)NCCC1CCCCC1

Procedure:
The desired amine was prepared using the method described in Example 1171A starting with cyclohexylacetic acid and t-butylamine. m/e (DCI/NH3) 184 (MH+)
Reaction SMILES: Cl[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][F:22])[N:15]=[N:14]3)=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:23].C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32]>CN(C)C=O>[CH2:31]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([F:12])=[C:7]([N:13]3[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][F:22])[N:15]=[N:14]3)[CH:6]=2)[CH:11]=[CH:2][C:3]1=[O:23])[CH3:32]
Reactant: O=C1Nc2cc(-n3nnn(CCCF)c3=O)c(F)cc2CC1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)ccc2cc(F)c(-n3nnn(CCCF)c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of 1.8 g (0.0052 mole) of 1-(3-chloro-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one and 1.1 g (0.0079 mole) of potassium carbonate in 50 mL of dimethylformamide was stirred at room temperature for 30 minutes. To this solution was added 1.6 g (0.011 mole) of 2-iodoethane, and the reaction mixture was stirred at room temperature for one hour, then was heated at 40° C. for two days. The reaction mixture was heated at 70° C. for four hours, then was cooled and poured into icewater. This mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane (75:25), to yield 0.77 g of 1[1 -ethyl-6-fluoroquinolin-2(1H)-one-7-yl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one as an oil.