Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[N:18][CH:19]=3)=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:37][C:38]1([F:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:37][C:38]1([F:44])[CH2:43][CH2:42][N:41]([C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[C:14]([C:10]3[CH:9]=[C:8]4[C:13](=[N:12][CH:11]=3)[N:4]([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6][CH2:7]4)[CH:19]=[N:18][CH:17]=2)[CH2:40][CH2:39]1
Reactant: FC1(F)CCNCC1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(CC(=O)O)c3)cnc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N1CCCc2cc(-c3cncc(CC(=O)N4CCC(F)(F)CC4)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a suspension of [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid (25 mg, 0.080 mmol) in DMF (1.5 mL) is added 1,1′-carbonyldiimidazole (14 mg, 0.088 mmol) and the mixture is stirred at room temperature for 16 h. 4,4-Difluoro-piperidine hydrochloride salt (15 mg, 0.096 mmol) and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) are added and stifling continues for an additional 16 h. H2O is added and the resulting precipitate is collected by filtration to afford 21 mg of the titled product.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][N:24]3[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]3)=[CH:21][C:20]=2[F:34])=[N:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1.O>[CH2:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)=[CH:21][C:20]=2[F:34])=[N:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1CN(Cc2ccc(C#Cc3ccc(Cc4ccccc4)cn3)c(F)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CN(Cc2ccc(C#Cc3ccc(Cc4ccccc4)cn3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of lithium hydroxide hydrate (28.4 mg, 677 μmol) and methyl 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate (77.9 mg, 188 μmol) in THF (2.7 mL) and water (0.69 mL) was stirred at 25° C. for 3 h. The reaction mixture was then partially concentrated in vacuo (to remove THF), water (1.5 mL) was added, and the resulting solution was sonicated for 1 min. The reaction solution was subsequently acidified with 1.0N HCl (670 μL), brought to pH 6 with 1M Na2HPO4/NaH2PO4 phosphate buffer (1.0 mL), and sonicated. The resulting precipitate was collected by vacuum filtration, washed with water (3.0 mL), and dried in vacuo to provide 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 400.2; Observed: 401.1 (M++1).
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH:11]([C:13]1(O)[C:18]([Cl:20])([Cl:19])[CH2:17][CH2:16][CH2:15][C:14]1([Cl:22])Cl)=[CH2:12].[OH-].[Na+]>O>[Cl:22][C:14]12[O:8][CH:15]1[CH2:16][CH2:17][C:18]([Cl:20])([Cl:19])[CH:13]2[CH:11]=[CH2:12]
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: C=CC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 90 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 1.14 g (4.32 mmol) of pure alcohol 1k, 12 cm3 of distilled water and 0.5 g (12.5 mmol) of sodium hydroxide; reaction time was 1 h 15 min; ether extraction (4×25 cm3); the crude product was employed as such (crude yld=90.5%) or purified by flash chromatography on silica (eluent: ether/petroleum ether=3/97): 0.88 g of epoxide 2i were obtained, that was a 90% yield (macrobore GC purity>98.6%) MW: 227.519; 1H NMR: 6.75-6.30 (m, 1H); 5.80-5.45 (m, 2H); 3.00-1.25 (m, 6H). 13C NMR: 126.1 (C7); 123.1 (C8); 88.35 (C3); 85.5 (C1); 70.0 (C2); 39.75 (C4); 32.4 (C6); 18.3 (C5). IR in cm-1 (film): 1080-940-875-785-735.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([F:22])[CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O.[Cl-].[Na+].O>[Cl:21][C:20]1[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[CH:13][C:14]([F:22])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(Oc2cc(F)c(C(=O)O)cc2Cl)CC1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To a solution of 4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoic acid (2.95 g, 8.92 mmol) in acetone (100 mL) was added 3 M hydrochloric acid (80 mL). The solution was heated to reflux for 17 hours and cooled to ambient temperature. The mixture was diluted with brine (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50% to afford the title compound as a colorless solid (1.14 g, 45%): 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=7.6 Hz, 1H), 6.77 (d, J=11.9 Hz, 1H), 4.82 (br s, 1H), 2.81-2.70 (m, 2H), 2.41-2.35 (m, 4H), 2.15-2.03 (m, 2H) (OH not observed); MS (ES−) m/z 285.1, 287.1 (M−1).
Reaction SMILES: [CH2:1]([CH:11]([C:17]([O-:19])=O)[C:12]([O:14]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][NH2:26]>C(O)C>[CH2:1]([CH:11]1[C:12](=[O:14])[NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20][C:17]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC(C(=O)[O-])C(=O)OCC
Reactant: NCCNCCN
Solvent: CCO
Product: CCCCCCCCCCC1C(=O)NCCNCCNC1=O
Yield: 62.1 %

Procedure:
A one litter round bottomed flask was charged with 0.076 mol (22.80 g) of ethyl α-decylmalonate (from above), 0.076 mol (7.74 g) diethylene triamine and 500 ml absolute ethanol. The mixture was refluxed for 42 days. During this period two ml aliquotes of solution were removed by hyperdermic syringe on days 7,15,22, and 37 for NMR analysis to determine the completeness of the reaction. After termination of the reflux, the ethanol was removed under reduced pressure and the product recrystallized from cold acetonitrile to yield 14.71 grams of a white heavy precipitate representing approximately a 62.1% conversion and having NMR characterizations in CDCL3, with signals reported in ppm downfield relative to TMS:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][C:37]2[CH:38]=[C:39]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][NH2:50])[CH:44]=3)[CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CCOC(C)=O.ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([NH:50][CH2:49][C:45]3[CH:44]=[C:43]([C:39]4[CH:40]=[CH:41][CH:42]=[C:37]([CH2:36][CH:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[CH:38]=4)[CH:48]=[CH:47][CH:46]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CC3CCN(C)CC3)c2)c1
Yield: 46.7 %

Procedure:
A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (77 mg, 0.198 mmol), (({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine (64.1 mg, 0.218 mmol), HATU (90 mg, 0.238 mmol), triethylamine (0.080 mL, 0.574 mmol) and dichloromethane (DCM) (3 mL) was stirred overnight at room temperature. The reaction was diluted with EtOAc; washed in turn with saturated aqueous NaHCO3, then saturated aqueous NaCl. The organic phase was dried (Na2SO4) and evaporated to a residue (185 mg). The residue was purified on a Gilson HPLC on RP column using a CH3CN—H2O (0.1% TFA) gradient [10-80%]. Fractions containing the desired product were combined and reduced to a small volume, and then treated with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2×); the combined extracts were washed with saturated aqueous NaCl and dried (Na2SO4), then solvent was evaporated of to give a glassy solid (61.6 mg). LC-MS m/z 666.6 (M+H)+, 0.75 min (ret time).
Reaction SMILES: O[CH:2]1C[CH2:5][N:4](C2C=CC(O)=CC=2)[CH2:3]1.[C:14]([O-])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:23].[OH2:24]>>[OH:24][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH2:5][NH:4][CH2:3][CH:2]=2)=[CH:16][CH:17]=1.[ClH:23]
Reactant: O
Reactant: Oc1ccc(N2CCC(O)C2)cc1
Reactant: O=C([O-])c1ccccc1
Agent: Cl
Product: Oc1ccc(C2=CCNC2)cc1

Procedure:
3.0 g (0.01 mol) of 3-hydroxy-(4-hydroxyphenyl)pyrrolidine·benzoate are dissolved in 100 ml of water. The solution is then brought to pH 1 with concentrated hydrochloric acid. The benzoic acid precipitated is extracted with ether and the clear aqueous solution evaporated. The solid residue is recrystallized from ethanol. There is obtained 3-(4-hydroxyphenyl)-3-pyrroline·HCl in the form of light beige crystals, mp 222° C. (from ethanol).
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])([CH3:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH3:8][C:2]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:11])([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: CC(C)(CCC(=O)O)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CCCO)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 4-methyl-4-(p-nitrobenzyloxycarbonyl)aminovaleric acid (14.0 g) and triethylamine (5.25 g) in tetrahydrofuran (280 ml), ethyl chloroformate (5.64 g) was added with ice-cooling and then stirred for 30 minutes. The resulting triethylamine hydrochloride was removed by filtration. To filtrate was added sodium borohydride (5 g) in water (90 mg) with ice-cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated to a volume of 120 ml in vacuo and extracted with dichloromethane. The dichloromethane layer was washed with diluted hydrochloric acid and then water, dried over anhydrous sodium sulfate and evaporated in vacuo to give an oily residue which was then purified by silica gel chromatography to give 4-methyl-4-(p-nitrobenzyloxycarbonyl)aminopentanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:24]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccco4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
Route 2: 2-(4-aminophenyl)-6-methyl benzothiazole (2.0 gm, 8.3 mmole) and 2-Furoyl chloride (1.086 gm., 8.32 mmole) were suspended in methylene chloride (30 ml, anhydrous). triethylamine (1.24 gm., 12.25 mmole) was added to the reaction mixture with stirring at room temperature for 2 days. (pH 7.0–7.2). Methylene chloride (50 ml) was added to the reaction mixture, and the reaction mixture extracted with 1 N HCl (50 ml) to separate a solid. The solid was filtered and washed with water to yield 1.3 gm. (46%) of the desired compound. The product was crystallized from MeOH to obtain 0.99 gm. mp. 238–240° C. 1H and 13C NMR were consistent with the expected product. TLC showed one spot (5% MeOH—CH2Cl2 as developing solvent on silica gel plate).
Reaction SMILES: C1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3]N=1.[CH3:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=3)[N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]=2[CH2:16]1>CC(C)CCO>[CH2:22]1[CH2:23][CH2:24][CH:19]([N:18]=[C:13]=[N:12][CH:11]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:20][CH2:21]1.[CH3:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=3)[N:18]([CH2:29][C:30]([O:32][CH2:3][CH2:4][CH:5]([CH3:6])[CH3:13])=[O:31])[C:17]=2[CH2:16]1
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CN(C)CC1
Solvent: CC(C)CCO
Product: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)OCCC(C)C)CN(C)CC1

Procedure:
Method for the preparation of compound 19 [isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate]: p-tolylhydrazine is alkylated with ethyl 2-bromoacetate to give the substituted phenylhydrazine, ethyl 2-(1-p-tolylhydrazinyl)acetate (III). The reaction of III with 4,4-dimethoxy-N-methylbutan-1-amine gives the indole derivative ethyl 2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate (V). Effecting the indole to standard Pictet Spingler conditions with formaldehyde gives the 1-carboline intermediate (VI) ethyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. Following treatment of VI with base the acid (VIII) 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetic acid is obtained. The treatment of this acid with DCC or other standard coupling reagents with 3-methylbutan-1-ol gives compound 19 isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: Cl[C:2]1[N:3](C)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CO.[Pd]>[C:12]1([C:4]2[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(C)c1Cl
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Reaction time: 6 h
Yield: 97 %

Procedure:
Ethyl 2-chloro-1-methyl-5-phenyl-1H-pyrrole-3-carboxylate (2.4 g, 9.1 mmol) and 10% Pd/C (100 mg) was dissolved in methanol (50 ml) at room temperature. The reaction mixture was hydrogenated for 6 hrs at room temperature and the resulting solution was filtered. After evaporated under reduced pressure, the residue was purified with normal phase preparative column chromatography to produce title compound (1.9g, 91%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[I:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([I:31])[CH:33]=2)[CH:6]=1
Reactant: BrCc1cccc(I)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(I)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.50 g, 0.0012 mol) in DMF (10 mL), was added 3-iodobenzyl bromide (0.36 g, 0.0012 mol) and powdered potassium carbonate (1.16 g, 0.0084 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.6 g in 81% yield. 1H NMR (CDCl3) δ 7.48 (d, 1H), 7.42 (s, 1H), 7.24 (m, 5H), 7.15 (m, 6H), 6.99 (d, 1H), 6.86 (m, 2H), 6.65 (s, 1H), 6.63 (dd, 1H), 4.16 (t, 1H), 3.67 (s, 3H), 3.60 (t, 2H), 3.58 (s, 2H), 3.52 (s, 2H), 3.05 (d, 2H), 2.61 (t, 2H), 1.81 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.5, 144.7, 143.7, 139.2, 137.3, 136.6, 131.2, 130.9, 129.8, 129.7, 129.6, 129.4, 127.8, 122.7, 116.9, 114.5, 95.6, 66.9, 61.1, 59.9, 53.5, 51.8, 51.1, 42.7, 28.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O)=[CH:28][CH:27]=1.C(N=C=NCCCN(C)C)C>O1CCOCC1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]2[N:35]=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:9]3=[O:17])[O:15][N:37]=2)=[CH:30][CH:31]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: [H]/N=C(/CCc1ccc(Cl)cc1)NO
Agent: CCN=C=NCCCN(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1N(Cc2nc(CCc3ccc(Cl)cc3)no2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the product of Example 58D (225 mg, 0.679 mmol) and the product of Example 165A (135 mg, 0.679 mmol) in 1,4-dioxane (4 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.120 mL, 0.679 mmol) via syringe. The reaction was stirred at ambient temperature for 2.5 hours, then heated to 60° C. for 44 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate, and washed with 3 N aqueous HCl resulting in a homogeneous solution. Brine was added to force the phase separation. The organic layer was separated and washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes) yielded the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.27 (m, 4H), 7.27-7.21 (m, 2H), 7.15-7.07 (m, 2H), 7.07-6.96 (m, 4H), 4.79 (s, 2H), 3.46 (t, J=6.4, 2H), 3.00 (s, 4H), 2.80 (t, J=6.4, 2H); MS (ESI+) m/z 511 (M+NH4)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]2[NH:11][C:12]([C:14]3[N:15]([CH3:27])[CH:16]=[C:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:18]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)=[O:4].Cl>[OH-].[Na+].O.O1CCOCC1>[C:23]([O:22][C:20]([NH:19][C:17]1[CH:18]=[C:14]([C:12]2[NH:11][C:9]3=[N:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[C:8]3[N:13]=2)[N:15]([CH3:27])[CH:16]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1ccc2nc(-c3cc(NC(=O)OC(C)(C)C)cn3C)[nH]c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1-c1nc2ccc(C(=O)O)nc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
Compound 8 (60 mg, 0.6 mmol) was dissolved in 0.2 M NaOH in H2O/dioxane 1:1 (7 mL) and stirred for 5 h at r.t. while the solution turned orange. The solution was cooled to 0° C. and 1N HCl was added dropwise until pH 1-2, while an orange precipitate developed. The product was separated by centrifugation, the supernatant removed, and the formed precipitate washed with cold H2O (2×2 mL). Lyophilization afforded 46 mg (81%) of 9 as an orange solid. Data of 9: UV (MeOH): λmax 359. 1H NMR (300 MHz, DMSO-d6): δ 1.46 (s, 9H), 4.05 (s, 3H), 7.01 (brs, 1H, D2O exchange), 7.15 (s, 1H), 7.98 (m, 3H), 9.30 (s, 1H, D2O exchange). 13C NMR (75 MHz, DMSO-d6): δ 28.96, 37.47, 79.21, 106.38, 118.65, 119.93, 120.44, 122.32, 124.99, 141.58, 150.32, 153.38, 166.53. MS (ESI): m/z (rel intensity) 358 (100). HRMS (FAB): m/z calcd for C17H20N5O4, 358.1515; found, 358.1506.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:30])[NH:21][C:22]([CH3:29])=[CH:23][C:24]=1[CH:25]([CH2:27][CH3:28])[CH3:26]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:30])[NH:21][C:22]([CH3:29])=[CH:23][C:24]=2[CH:25]([CH2:27][CH3:28])[CH3:26])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CCC(C)c1cc(C)[nH]c(=O)c1CN
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Product: CCC(C)c1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.50 g, 1.77 mmol) and 3-(aminomethyl)-4-(sec-butyl)-6-methylpyridin-2(1H)-one (0.446 g, 2.296 mmol). The product was collected as 0.81 g (98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H), 8.62 (t, J=4.7 Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 5.96 (s, 1H), 5.05 (quin, J=6.6 Hz, 1H), 4.41 (d, J=4.3 Hz, 2H), 2.95 (q, J=7.1 Hz, 1H), 2.15 (s, 3H), 1.48 (m, 8H), 1.07 (d, J=6.6 Hz, 3H), 0.74 (t, J=7.3 Hz, 3H). LC-MS(ES) [M+H]+ 459.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][C@H:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[NH+]1C=C[CH:27]=[CH:26][CH:25]=1.COC(OC)(C)C>C(Cl)(Cl)Cl>[CH2:8]([C@@H:7]1[O:11][C:26]([CH3:27])([CH3:25])[N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[C@H:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[C:21]([F:23])[CH:20]=1)[CH:9]=[CH2:10]
Reactant: C=CC[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reactant: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)OC
Product: C=CC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Alcohol (32) was stirred in chloroform with pyridinium p-toulenesulfonate and 2,2-dimethoxypropane to afford (33) as an amber oil after workup.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([OH:16])[CH2:15][CH2:14]C[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.BrC1C=C2C(=CC=1)[NH:23][CH:22]=C2.[Li]C(C)(C)C.CCCCC.C1(=O)CCCCC1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([OH:16])[CH2:15][CH2:14][N:23]([CH3:22])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OC1(c2ccc3[nH]ccc3c2)CCCCC1
Agent: [Li]C(C)(C)C
Solvent: O=C1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN1CCC(O)(c2ccc3[nH]ccc3c2)CC1

Procedure:
1-(1H-Indol-5-yl)cyclohexanol (1.95g 35%): from 5-bromo-1H-indole (5 g, 25.5 mmol) with KH (1.127 g, 28.1 mmol) in THF at −10° C., then treated with 1.7 M t-BuLi in pentane (37.5 mL, 63.8 mmol) and cyclohexanone (5.68 mL, 54.8 mmol) at −78° C.