Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH2:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1coc(-c2ccccc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1coc(-c2ccccc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 25 %

Procedure:
This compound was synthesized from 2-(2-phenyloxazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mgs, yield 25%). 1H NMR (CDCl3) δ 8.59 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.05 (m, 2H), 7.62-7.56 (m, 3H), 7.43 (m, 2H), 3.84 (m, 2H), 2.93 (m, 2H). MS (ESI) m/z: Calculated for C21H15F3N4O3: 428.11. found: 429.1 (M+H)+.
Reaction SMILES: [C:1]([N:3]([CH3:9])[C:4](=[O:8])[CH:5](Br)[CH3:6])#[N:2].C1(C(C2[C:23]([CH2:24][O:25][CH2:26][C:27]3[C:32](C4C(=CC=C(O)C=4)O)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=[CH:20][CH:19]=2)=CC(=CC=1)O)O.C(=O)([O-])[O-:42].[K+].[K+]>CN(C)C=O>[C:1]([N:3]([CH3:9])[C:4](=[O:8])[CH:5]([O:42][C:21]1[CH:20]=[CH:19][C:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)[CH3:6])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC(Br)C(=O)N(C)C#N
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(OCc2ccccc2)cc1)C(=O)N(C)C#N
Yield: 62.8 %

Procedure:
With efficient stirring, B 19.1 g (0.1 mole) of 2-bromopropionic acid N-cyano-N-methylamide are added dropwise to a solution of 20.0 g (0.1 mole) of hydroquinone monobenzyl ether and 16.5 g (0.12 mole) of potassium carbonate in 200 ml of dimethylformamide. After the slightly exothermic reaction has subsided, the reaction mixture is heated for 3 hours to 40° C. The precipitated salts are then removed by filtration and the filtrate is concentrated by evaporation. The residue is dissolved in ether and the ether solution is extracted with dilute sodium hydroxide solution. The organic phase is dried over sodium sulfate, the solvent is evaporated off and the residue is distilled in vacuo, affording 19.5 g (63% of theory) of 2-(4-benzyloxyphenoxy)propionic acid N-cyano-N-methylamide with a melting point of 56°-58° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[CH3:15].CC(O)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:15]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(N)cc1C
Yield: 103.4 %

Procedure:
A solution of (2-methyl-4-nitro-phenoxy)-acetic acid methyl ester (36.3 g, 161 mmol) in MeOH (400 ml) and AcOH (11.2 ml, 177 mmol) was hydrogenated in the presence of 10% Pd/C (3.63 g) for 7 h. After removal of the catalyst the reaction was evaporated, dissolved in toluene and evaporated (5×) to give 32.5 g of (4-amino-2-methyl-phenoxy)-acetic acid methyl ester as a brown crystallin residue, MS: 196 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-2-methyl benzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, 3-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-methylbenzenesulfonamide (percentage yield: 90%), was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:16].[C:17](=O)([O:20]C)[O:18][CH3:19].[H-].[Na+]>CO>[O:16]=[C:10]1[C:2]2([CH2:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:17]([O:18][CH3:19])=[O:20]
Reactant: COC(=O)OC
Reactant: O=C1CCCCCC12Cc1ccccc1C2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCCC2(Cc3ccccc3C2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Example 19A (1.8 g, 8.40 mmol) in dimethyl carbonate (7.1 mL, 84 mmol) was treated with sodium hydride (60% dispersion in mineral oil, 0.672 g, 16.80 mmol) and a catalytic amount of MeOH (2 drops), then the mixture was heated at reflux. After 3 hours, the reaction was cooled to room temperature, and then it was quenched with 2N HCl. The mixture was extracted with ether, then the extracts were dried (Na2SO4) and evaporated. Purification by silica gel chromatography (10 to 25% EtOAc-hexane, eluant) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.10-7.21 (m, 4H), 4.25 (dd, J=11.1, 2.8 Hz, 1H), 3.57 (s, 3H), 3.51 (d, J=15.9 Hz, 1H), 3.15 (d, J=15.9 Hz, 1H), 3.00 (m, 1H), 2.60 (d, J=16.3 Hz, 1H), 2.09 (m, 1H), 1.90 (d, J=5.2 Hz, 2H), 1.72-1.85 (m, 2H), 1.44-1.56 (m, 2H), 1.02-1.15 (m, 1H). MS (DCI+) m/z 273 (M+H), 290 (M+NH4).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[CH2:28]([Mg]Br)[CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][C:8](=[O:27])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:11]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:12]=2)[CH:15]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Reactant: CCCCC[Mg]Br
Product: CCCCCC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and pentylmagnesium bromide using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 0.81 (t, 3H), 1.17 (m, 6H), 1.51 (m, 2H), 2.28 (s, 3H), 2.37 (s, 3), 4.04 (s, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.23 (d, J=7.3 Hz, 2H), 7.55 (m, 4H). Mass spectrum m/e 335 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]>C(O)(C)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=[C:6]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=1
Reactant: CC(C)(C)CN
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1

Procedure:
After dropwise adding 5.00 g (27.26 moles) of 2,4,6-trichloropyrimidine to the solution of 11.88 g (136.3 mmoles) of 1-amino-2,2-dimethylpropane in 50 ml of isopropanol while cooling and stirring, the reaction mixture is boiled under reflux for 20 hours, then evaporated. The evaporation residue is distributed between 80 ml of chloroform and 25 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography by using a mixture of hexane and ethyl acetate as eluent on a silica gel column. By carrying out the elution with a 99:1 mixture, 6-chloro-2,4-bis(2,2-dimethylpropylamino)pyrimidine is obtained which is recrystallized from hexane to give a yield of 5.74 g (73.9%), m.p.: 95°-97° C.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ON1C2C=CC=CC=2N=N1.[OH:60][CH2:61][C@@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[NH2:63].C(N=C=NC(C)C)(C)C>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:63][C@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[CH2:61][OH:60])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
A mixture of 27-linoleoyloxyheptacosanoic acid (5 g, 7.2 mmoles), chloroform (90 ml), dried 1-hydroxybenzotriazole (3.2 g, 27.3 mmoles), phytosphingosine (3.07 g, 9.7 mmoles) and N,N'-diisopropylcarbodiimide (2.2 ml, 14.1 mmoles) was stirred under nitrogen for 90 minutes at 45° C. and then overnight at room temperature. After washing with 50 ml of a 1N hydrochloric acid solution and brine and filtration the organic layer was concentrated. After addition of hot isopropanol (150 ml) the mixture was filtered while still hot. After cooling down the precipitate formed was filtered off, washed with isopropanol (30 ml), acetone (10 ml) and dried giving 3.7 g of the title compound.
Reaction SMILES: [Li].[CH2:2]([N:9]1[CH2:17][C@H:16]2[C@H:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:14][C:15]2=[O:18])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].O>O1CCCC1.C(OCC)(=O)C>[CH2:2]([N:9]1[CH2:17][C@H:16]2[C@H:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:14][C@H:15]2[OH:18])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: [BH4-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
4.0 cm3 of a 1M solution of lithium tri-sec-butylboro-hyride in tetrahydrofuran is added over 5 minutes to a solution, cooled to 0° C., of 1.3 g of (3aR,7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone in 6.0 cm3 of tetrahydrofuran. After stirring for 3 hours at 0° C., 0.5 cm3 of the 1M solution of borohydride is again added to the reaction mixture. After 1 hour at 0° C., followed by the addition of 50 cm3 of water and 50 cm3 of ethyl acetate, the organic phase is decanted, washed with 20 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm3 of diisopropyl oxide, the crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR,4R,7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of white crystals; melting point 154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6]C)=[C:4]([N+:10]([O-])=O)[CH:3]=1.NN.[CH3:15]O>[Ni]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH3:15])([NH2:6])[CH:4]([NH2:10])[CH:3]=1
Reactant: CO
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Product: CC1(N)C=CC(Cl)=CC1N
Yield: 84 %

Procedure:
32.5 g (0.175M) of 4-Chloro-2-nitro-N-methylaniline of A above are added gradually to 24 g Raney-Nickel (wet) and 48 g hydrazine in methanol. A large amount of heat is generated. After the addition is complete, the solution is heated to reflux for 3 hours and filtered to remove the metal catalyst. The solvent is removed and the residue dissolved in methylene chloride. The methylene chloride solution is extracted with water and the mixture is filtered to remove the emulsion. The layers are separated and the methylene chloride layer is dried over anhydrous magnesium sulfate. After removal of the solvent, the residue is recrystallized from hexane. The substituted phenylenediamine weighs 22.6 g (84% yield) and has a melting point of 51°-2° C.
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:19](OC)(OC)OC.S(Cl)(Cl)=O>CO>[O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:19])=[O:6]
Reactant: COC(OC)OC
Reactant: O=C(O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoic acid (Example 11, A19, 50 mg, 0.19 mmol) and trimethyl orthoformate (60.7 mg, 3 eq.) were dissolved in methanol (4 mL), and thionyl chloride (68.1 mg, 3 eq.) was added dropwise. The reaction was stirred at room temperature for 3 h. The solvent were evaporated and the crude was treated with Dowex 1×8 OH to give the methyl 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoate A20 (36 mg, 69%). 1H NMR (400 MHz, CDCl3): 2.77 (s, 4H), 3.73 (s, 3H), 7.91 (dd, 1H), 8.33 (d, 1H), 8.54 (s, 1H), 8.59 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(Cl)Cl.C(OCC)C>[CH:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (18.5 mL, 2M in DCM, 37.0 mmol) in DCM (230 mL) was cooled with a dry ice/acetone bath. DMSO (5.15 mL, 72.6 mmol) was added dropwise via addition funnel and the reaction was stirred for 10 min. N-Boc-4-piperidinemethanol in DCM (20 mL) was added dropwise via addition funnel and the reaction was stirred for 15 min. TEA (17.0 mL, 122 mmol) was then added dropwise via addition funnel and the reaction was warmed to rt. The reaction was diluted with diethyl ether, washed with H2O and brine, dried (MgSO4) and concentrated to provide the title compound (5.36 g, 25.1 mmol, 100%, approximately 96% pure, used without further purification). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.34 (m, 3H), 1.37 (s, 9H), 1.75-1.83 (m, 2H), 2.87 (s, 2H), 3.78 (d, J=13.2 Hz, 2H), 9.56 (s, 1H).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[C:27]3[N:37](C(OC(C)(C)C)=O)[C:38]4[CH:39]=[CH:40][C:41]([Br:44])=[CH:42][C:43]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:52])[CH:22]=2)(OC(C)(C)C)=O.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[Br:44][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:27]1[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Br:52])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCCCBr)c21
Agent: c1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(OCCCCCN4CCOCC4)c4[nH]c5ccc(Br)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the starting indole is 5,7-diBOC-2,10-dibromo-6-(5-bromopentyloxy)indolo[2,3-b]carbazole and the reagent is morpholine. 1H-NMR (400 MHz, acetone-d6) δ ppm 8.68 (s, 1 H), 8.32 (d, J=2.4 Hz, 2 H), 7.48-7.41 (m, 4 H), 4.34 (t, J=6.8 Hz, 2 H), 3.56 (t, J=4.8 Hz, 4 H), 2.39-2.23 (m, 6 H), 1.98-1.87 (m, 2 H), 1.60-1.44 (m, 4 H); MS (ESI) m/z 584.1 (M−H)−
Reaction SMILES: C[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[Li][CH2:8][CH2:9]CC.C(O[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)(C)C>[NH4+].[Cl-]>[CH2:8]([N:5]1[C:6]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:2][CH:3]=[N:4]1)[CH3:9]
Reactant: [Li]CCCC
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cn[nH]c1
Agent: [Cl-]
Agent: [NH4+]
Product: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
At 0° C., to above solution of 4-methylpyrazole (˜50 mmol) was added n-BuLi (2.5M in hexane, 22 mL, 55 mmol). The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.2 g, 55 mmol). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (9.8 g, 89%) which was used without further purification. LCMS (ES) m/z 141 (M+H)+ for [RB(OH)2]; 1H NMR (CDCl3, 400 MHz) δ ppm 7.52 (d, J=2 Hz, 1H), 6.36 (d, J=2 Hz, 1H), 4.48 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H), 1.36 (s, 12H)
Reaction SMILES: Cl.C[NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O>[C:28]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]23[CH2:12][CH:13]4[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[CH:8][CH:9]=1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 18 h

Procedure:
A solution of the free base from 2.82 g. of the N-methyl-4-(1-adamantyloxy)aniline hydrochloride in 20 ml. pyridine was treated dropwise with 1.64 ml. ClCO2C2H5. Following 18 hours standing in the cold the mixture was poured into ice:H2O. This was extracted with Et2O and the organic layer washed in turn with H2O, cold 2.5 N HCl, H2O NaHCO3 and brine. The extract was then taken to dryness to leave behind N-methyl, N-carbethoxy-4-(1-adamantyloxy)aniline as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:15]([O:17][C:18]([C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:23]=[N:22][C:21]=1[C:34]([OH:36])=O)=[O:19])[CH3:16].P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:24]2[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[C:21]([C:34](=[O:36])[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:22]=[N:23]2)=[CH:31][CH:30]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1c(C(=O)O)nnn1Cc1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C(=O)N(C)c2ccccc2)nnn1Cc1ccc(OC)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Under the argon atmosphere, N-methylaniline (0.1 ml, 0.923 mmole) and pyridine (0.32 ml, 3.96 mmole) were added to a solution of 5-ethoxycarbonyl-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid (311 mg, 1.02 mmole) in methylene chloride (3 ml). To the reaction mixture, which had been cooled to -30° C., was added a solution of phosphorus oxychloride (192 mg, 1.25 mmole) in methylene chloride (0.5 ml). After the mixture was stirred at -30° C. for 1 hour, the reaction was quenched by adding water. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate and a saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give ethyl 1-(4-methoxybenzyl)-4(N-methyl-N-phenylcarbamoyl)-1,2,3-triazole-5-carboxylate as a yellow crystalline powder (329 mg, 90.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[NH:26][CH:25]=[C:24]([C:27](O)=[O:28])[CH:23]=2)[CH:17]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:66]1[CH2:70][CH2:69][C@H:68]([OH:71])[CH2:67]1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[C:12]1[CH:32]=[CH:31][CH:30]=[C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[NH:26][CH:25]=[C:24]([C:27]([N:66]4[CH2:70][CH2:69][CH:68]([OH:71])[CH2:67]4)=[O:28])[CH:23]=3)[CH:17]=2)[CH:13]=1
Reactant: O[C@H]1CCNC1
Reactant: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(-c4cc(C(=O)N5CCC(O)C5)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.12 mmol), HATU (55 mg, 0.14 mmol) and N,N-diisopropylethylamine (34 mg, 0.26 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of (S)-3-pyrrolidinol (16 mg, 0.18 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide as white solid. Yield: 40 mg, 69%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](Cl)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH:35][C:36](=[O:38])[CH3:37].O1CCCC1>O>[C:36]([N:35]([CH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=1)[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 5.0 g of product from Example 111, 0.683 g of washed 50% sodium hydride, 2.14 g of product from Example 12 and 100 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 1 hour, heated at reflux temperature for 18 hours and cooled to room temperature. The mixture is poured into water, extracted with chloroform and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 15-30% ethyl acetate/hexane) to give 2.93 g of the desired product.