Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:32][C:33](=[N:67][C:68](=[O:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:54]2[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([O:62][CH2:63][CH2:64]O)[C:55]=2[F:66])[C:42]2[NH:46][C:45](=[O:47])[N:44]([C:48]3[N:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[N:43]=2)=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.ClCCl>[NH2:32][C:33](=[N:67][C:68](=[O:75])[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:42]2[NH:46][C:45](=[O:47])[N:44]([C:48]3[N:49]=[CH:50][CH:51]=[CH:52][N:53]=3)[N:43]=2)[C:54]2[C:55]([F:66])=[C:56]([CH:57]=[C:58]([O:60][CH3:61])[CH:59]=2)[O:62][CH2:63][CH2:64][O:15][C:14](=[O:16])[C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[CH:36][CH:35]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OCCOC(=O)c2ccncc2)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under nitrogen atmosphere, triethylamine (0.348 mL) was added under ice-cooling to a mixture of 4-pyridinecarboxylic acid [CAS No. 55-22-1] (61.6 mg), TFFH (132 mg), and dichloromethane (5 mL), and the resulting mixture was stirred for 1 hour. To the mixture, a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 150 mg), DMAP (5 mg), and DMF (2.5 mL) was added dropwise. After stirring the resulting mixture at room temperature for 3 days, the solvent in the mixture was concentrated under reduced pressure. The residue obtained was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (188 mg).
Reaction SMILES: O.[Cl:2][C:3]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:4]=1[CH:5]=[O:6].[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:16]1[C:12]([C:8]2[CH:7]=[C:4]([CH:5]3[O:25][CH2:24][CH2:23][O:6]3)[C:3]([Cl:2])=[CH:10][C:9]=2[F:11])=[N:13][N:14]([CH3:22])[C:15]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C3OCCO3)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Yield: 61.2 %

Procedure:
In an apparatus equipped with a Dean-Stark trap for azeotropic removal of water, 2.4 g (7.0 mmoles) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde, 0.4 mL (7.7 mmoles) ethylene glycol and a catalytic amount of p-toluenesulfonic acid in 50 mL toluene was heated to reflux for 24 hours. The resultant mixture was concentrated and the residue purified by chromatography to give 1.65 g (61%) of 4-chloro-3-(4-chloro-5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a clear colorless oil; nD25 51.5348.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:19])C.[NH4+]>C(O)=O.O>[CH3:16][C:13]1[N:12]=[CH:11][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:19])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(COc2ccnc(Cl)c2)cn1
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: Cc1ccc(COc2cc[nH]c(=O)c2)cn1
Yield: 77.5 %

Procedure:
2-Chloro-4-((6-methylpyridin-3-yl)methoxy)pyridine (4.20 g, 17.9 mmol) and ammonium acetate (6.91 g, 89.7 mmol) were heated at 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO3 solution. The solid was filtered off to provide the title compound (3.0 g, 77%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.27-11.04 (br s, 1H), 8.51 (s, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.29-7.24 (m, 2H), 5.89 (d, J=7.2 Hz, 1H), 5.82 (s, 1H), 5.05 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:9](=[O:11])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[O:12][CH3:13])=[CH:18][CH:17]=1)#[N:14]
Reactant: COC(C(=O)O)c1ccc(O)cc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1

Procedure:
(RS)-(4-Hydroxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide. Colorless foam. MS 295.2 ([M−H]−)
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[F:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(F)cc3F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,4-difluorobenzoyl chloride: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:5][CH:6]=[C:7]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)[CH3:3].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:3][CH:2]([C:4]1[S:5][CH:6]=[C:7]2[CH2:11][NH:10][CH2:9][C:8]=12)[CH3:1]
Reactant: CC(C)c1scc2c1CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1scc2c1CNC2

Procedure:
A solution of 0.49 g (1.8 mmol) of 1-(1-methylethyl)5-(1,1-dimethylethoxy)carbonyl-5,6-dihydro -4H-thieno[3,4-c]pyrrole in 0.5 ml of trifluoroacetic acid is stirred for 30 min at a temperature in the region of 20° C. After evaporation of the solvent, 0.51 g of an oily product is obtained. Quantitative yield.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)C.ClC1C=CC(C2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][NH:22][N:21]=2)=CC=1>>[CH2:44]([N:41]([CH2:42][CH3:43])[CH2:40][CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:27]2[N:26]=[C:25]([C:24]3[C:4]([C:5]4[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=4)=[N:21][NH:22][CH:23]=3)[CH:30]=[CH:29][N:28]=2)=[CH:33][CH:34]=1)[CH3:45]
Reactant: CCOC(=O)c1cccc(C)c1
Reactant: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Product: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3cccc(C)c3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using ethyl-3-methylbenzoate (Aldrich 25,305-7) and 4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:21][C:22]([O-])(C)[CH3:23].[K+].C(Br)C=C>C(O)(C)(C)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH:22]=[CH2:21])[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CCC1=O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C=CCBr
Product: C=CCC1(C(=O)OCC)CN(C(=O)c2ccccc2)CCC1=O
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
1.16 g (4.22 mmol) of ethyl-1-benzoyl-4-oxo-3-piperidine carboxylate, 9 ml of tert-butanol and 0.57 g (4.93 mmol) of potassium tert-butylate (97 percent) were used at 25° C. and stirred for 30 minutes. Then 0.70 g (5.67 mmol) of allylbromide was instilled in 2 minutes. The mixture was stirred with reflux for 16 hours, the reaction mixture was concentrated by evaporation and divided between 30 ml of methylene chloride and 30 ml of water. The emulsion was adjusted to pH 7 with hydrochloric acid (1N). The phases were separated and the aqueous phase was extracted three more times with 30 ml of methylene chloride. The combined organic phases was dried with magnesium sulfate and concentrated by evaporation. 1.34 g of crude product was obtained which was purified by column chromatography. The yield was 0.850 g of pure ethyl-1-benzoyl-4-oxo-3-(2-propenyl)-3-piperidine carboxylate, which equals 64 percent. Data concerning the compound was:
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:36][C:37]([C:39]1[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=1)=[O:38])=[O:4].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:45][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:36][C:37]([C:39]1[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=1)=[O:38])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Temperature: 0 °C
Yield: 25 %

Procedure:
1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (0.289 mmol) was dissolved in tetrahydrofuran (2.0 mL), cooled to 0° C. and treated with 5% perchloric acid in acetic acid (8 mL) for 3 h. The material was carefully poured into saturated sodium bicarbonate and extracted into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (3×), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (35.8 mg, 27.9%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 3.0 (s, 3H), 3.06 (s, 3H), 3.73 (s, 3H), 3.83 (s, 3H), 7.05 (dt, J=7.0 Hz, J=1.0 Hz, 1H), 7.13 (bd, J=7.5 Hz, 1H), 7.30 (dd, J=1.5, J=7.0 Hz 1H), 7.61 (dd, J=1.5 Hz, J=7.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.73 (8.33 (d, J=7.5 Hz, 1H), 7.77 (br s, 1H), 7.81 (dd, J=2.0, J=8.5 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 8.19 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H), 10.07 (s, 1H), 11.83 (s, 1H). MS: m/z 496 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CC(C)CN
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: C1COCCO1
Product: CC(C)CNc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), isobutylamine (77 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a yellow foam (28 mg, 0.048 mmol, 22.59%). 1H NMR (400 MHz, DMSO-d6) ppm 0.87 (d, J=6.57 Hz, 7H), 1.76 (td, J=12.00, 3.79 Hz, 3H), 1.94-2.06 (m, 2H), 3.25-3.34 (m, 2H), 3.41-3.50 (m, 2H), 3.93 (dt, J=9.66, 2.12 Hz, 2H), 5.79-6.04 (m, 1H), 6.66 (d, J=1.26 Hz, 1H), 7.20-7.41 (m, 3H), 7.41-7.56 (m, 1H), 7.81 (t, J=1.77 Hz, 1H), 8.08 (d, J=5.30 Hz, 1H), 8.28 (s, 1H), 10.31 (s, 1H); MS (ESI): 558.0 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:4].O>C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([Br:1])[CH:14]=1)[CH3:4]
Reactant: CCOC(=O)CCc1ccc(OC)cc1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1ccc(OC)c(Br)c1

Procedure:
87.5 g of bromine are added dropwise at 25° C. over 3 hours to a solution of ethyl3-(4-methoxyphenyl)propanoate (113.9 g; 0.545 mol) in 900 ml of chloroform. The mixture is poured into water and the organic phase is separated out by settling of the phases and washed with 10% sodium hydrosulfite solution. After drying and evaporating off the solvents, a yellow oil is collected (154 g; 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[CH:16][C:9]=12)([O-])=O>[Pd].CCO.CCOC(C)=O>[NH:14]1[C:10]2=[N:11][CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:5]=[C:4]([NH2:1])[C:19]([NH2:20])=[CH:18][CH:17]=3)=[C:9]2[CH:16]=[CH:15]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1N

Procedure:
A solution of 4-(3,4-dinitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine (Step C, 0.284 g, 0.95 mmol) in a 2/1 EtOH/EtOAc (30 mL) mixture with a catalytic amount of 10% Pd/C was stirred under H2 at RT and atmospheric pressure. The catalyst was removed by filtration and the solvents were removed under vacuum. The crude material was purified on silica gel using a CH2Cl2/EtOH/NH4OH gradient (100/0/0 to 90/10/1) to give 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-benzene-1,2-diamine.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])[CH2:10][CH2:9]1)[CH3:7].CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:6]([CH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH3:2])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])[CH2:12][CH2:13]1)[CH3:7]
Reactant: [Li]CCCC
Reactant: CCC1CCC(c2ccc(-c3ccc[se]3)c(F)c2F)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCC1CCC(c2ccc(-c3ccc(C)[se]3)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2.2 ml (13.0 mmol) of TMP are initially introduced at −15° C. in 15 ml of diethyl ether, and 8.2 ml (13.0 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min, a solution of 3.5 g (9.9 mmol) of 2-[4-(4-ethyl-cyclohexyl)-2,3-difluorophenyl]selenophene in 35 ml of diethyl ether is metered in at 0° C., and the mixture is stirred at RT for 2 h. The batch is cooled to −70° C., and 3.0 ml (48.2 mmol) of methyl iodide are added. The mixture is warmed to RT and stirred for 24 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is briefly stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from ethanol. 2-[4-(4-Ethylcyclohexyl)-2,3-difluorophenyl]-5-methylselenophene is obtained as a solid having an m.p. of 63° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:44]=[O:45])=[C:24]2[C:28]=1[N:27]=[C:26]1[N:29]([C:33]3[C:34]([CH2:42][CH3:43])=[N:35][C:36]([CH3:41])=[N:37][C:38]=3[CH2:39][CH3:40])[CH2:30][CH2:31][CH2:32][N:25]21.C[Si](C)(C)[C:48]([F:51])([F:50])[F:49].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][C:20]1[C:28]2[N:27]=[C:26]3[N:29]([C:33]4[C:34]([CH2:42][CH3:43])=[N:35][C:36]([CH3:41])=[N:37][C:38]=4[CH2:39][CH3:40])[CH2:30][CH2:31][CH2:32][N:25]3[C:24]=2[C:23]([CH:44]([OH:45])[C:48]([F:51])([F:50])[F:49])=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCc1nc(C)nc(CC)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCc1nc(C)nc(CC)c1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.31 mL, 0.31 mmol) was added dropwise to a stirred solution of 9-chloro-1-(4,6-diethyl-2-methylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (601 mg, 1.57 mmol) and trimethyl(trifluoromethyl)silane (670 mg, 4.71 mmol) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at 0° C. for 90 min. 1N hydrochloric acid (4.0 mL) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 10 min. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (684 mg, 1.51 mmol, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:21]2[O:25][CH:24]=[N:23][CH:22]=2)[NH:14]S(C(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(Cl)[Cl:27].Cl>CCOCC>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:21]2[O:25][CH:24]=[N:23][CH:22]=2)[NH2:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)(C)S(=O)NC(c1ccc(OC(F)(F)F)c(F)c1)c1cnco1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: NC(c1ccc(OC(F)(F)F)c(F)c1)c1cnco1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of 55 (570 g, 1.5 mol) and DCM (10 mL) was added HCl (3.74 mL, 1.5 mol) and the solution stirred for 30 min. The reaction mixture was added dropwise to a stirred solution of ether. The solids were filtered and washed with Et2O to afford 223 mg (47.6%) of (3-fluoro-4-(trifluoromethoxy)phenyl)(oxazol-5-yl)methanamine hydrochloride (56).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:17](=O)[CH3:18]>CO.[Pd]>[CH2:17]([NH:2][C@H:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:18]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 110.6 %

Procedure:
To a solution of (R)-tert-butyl 2-amino-2-phenylacetate hydrochloride (0.25 g, 1.026 mmol) in MeOH (10.26 mL) was added 10% Pd/C (0.080 g, 1.026 mmol). The resulting mixture was cooled to 0° C., and acetaldehyde (0.576 mL, 10.26 mmol) was added. The resulting mixture was stirred at 0° C. for 10-15 mins, the ice bath was removed, and the mixture was placed under a hydrogen balloon and stirred at rt for 45 mins. The mixture was filtered through celite, washed with methanol, and the filtrate was concentrated in vacuo to give the title compound (0.267 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.Br[CH:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:6]=1)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCC(=O)c1ccc(O)cc1
Reactant: CCCCCCC(Br)C(=O)OCC
Product: CCCCCCCC(=O)c1ccc(OC(CCCCCC)C(=O)OCC)cc1
Yield: 77.5 %

Procedure:
1-[4-Hydroxyphenyl]-1-octanone (440 mg, 2.0 mmol) and ethyl (RS)-2-bromooctanoate (552 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Octanoylphenoxy]octanoate (605 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 4.66 (dd, J=5.1, 7.4 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 1.88-2.02 (m, 2H), 1.70 (tt, J=7.2, 7.2 Hz, 2H), 1.41-1.56 (m, 2H), 1.25-1.37 (m, 14H), 1.23 (t, J=7.1 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.41, 171.48, 161.81, 131.01, 130.54 (2C), 114.77 (2C), 76.75, 61.62, 38.56, 32.90, 31.94, 31.78, 29.60, 29.38, 29.07, 25.33, 24.80, 22.85, 22.75, 14.39, 14.31, 14.26. The resulting ester (605 mg, 1.6 mmol) was saponified with lithium hydroxide (186 mg, 7.8 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Octanoylphenoxy]octanoic Acid (487 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 9.70 (br s, 1H), 7.89 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.69 (dd, J=5.9, 6.6 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 1.95-2.01 (m, 2H), 1.67 (tt, J=7.2, 7.2 Hz, 2H), 1.43-1.58 (m, 2H), 1.24-1.37 (m, 14H), 0.851 (t, J=6.8 Hz, 3H), 0.849 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 200.38, 176.08, 161.84, 130.85, 130.78 (2C), 114.83 (2C), 76.20, 38.56, 32.79, 31.93, 31.76, 29.57, 29.35, 29.05, 25.34, 24.92, 22.84, 22.74, 14.29, 14.23. The acid (500 mg, 1.4 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Octanoylphenoxy]octanoate (404 mg, 76%) as a white solid. mp 165-170° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.58 (dd, J=6.1, 6.3 Hz, 1H), 2.91 (t, J=7.3 Hz, 2H), 1.91-1.96 (m, 2H), 1.62-1.69 (m, 2H), 1.44-1.58 (m, 2H), 1.25-1.39 (m, 14H), 0.87-0.90 (m, 6H); 13C NMR (101 MHz, CD3OD): δ 200.50, 176.40, 162.96, 130.28 (2C), 129.94, 114.71 (2C), 78.38, 38.00, 32.98, 31.79, 31.74, 29.27, 29.20, 29.05, 25.50, 24.79, 22.56, 22.51, 13.36, 13.34; LRMS (ESI): m/z 769 (M2H+), 748 (2M−Na++2H+), 363 (M−Na++2H+); HPLC: 3 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]([CH3:21])=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]([CH3:21])=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCC(N)CC1
Reactant: Cc1nc(C)c(Cl)c(Sc2sc(C(=O)O)cc2[N+](=O)[O-])c1Cl
Agent: Cl
Product: Cc1nc(C)c(Cl)c(Sc2sc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])c1Cl

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-dichloro-2,6-dimethylpyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid from the above (200 mg, 0.53 mmol) and 1-methylpiperidin-4-amine hydrogen chloride salt (72.0 mg, 0.63 mmol). The title compound was obtained as a solid (180.0 mg, 72% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.63 (1H, m), 8.49 (1H, s), 3.58 (1H, m), 2.75 (2H, m), 2.65 (6H, s), 2.14 (3H, s), 1.92 (2H, m), 1.72 (2H, m), 1.49 (2H, m). MS m/z: 475.18, 477.17 [M+H]+.