Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=[CH:16]3)=[N:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[N:3]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccccc3C3=NC(C)(C)CO3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2ccccc2-c2ccc3[nH]ccc3c2)=N1
Reaction time: 3 h
Yield: 74.5 %

Procedure:
5-[2-(4,4-Dimethyloxazolin-2-yl) phenyl ]-1-triisopropylsilylindole (1.48 mmoles, 661 mg) in 5 ml THF was treated at 0°C. with tetrabutylammonium fluoride (2.22 mmoles, 2.22 ml of 1.0N solution in THF). The solution was stirred for 3 hours, poured into 30 ml water, and extracted with ether. The organic layer was dried and concentrated. The oil was triturated with ether/hexane, and the solid was isolated by filtration. The reaction yielded 320 mg of 5-[2-(4,4-dimethyloxazolin-2yl)phenyl]indole. (MS)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9](O)=[O:10]>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][CH:9]=[O:10])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=CO
Product: O=CNc1ccc(Cl)nc1

Procedure:
Was prepared according to Example 2 from 5-amino-2-chloropyridine and formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[CH:28][CH:27]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]4)=[CH:30][CH:31]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(N)cc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cnc(Nc3ccc(C4CCCCN4)cc3)nc2n2ccnc2n1-c1ccccc1Cl
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate (0.059 g, 0.213 mmol) was heated in a capped vial at 120° C. for 1 hour. The reaction mixture was treated with ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. for 5 hours, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 1.89-1.72 (m, 2H), 2.16-1.96 (m, 4H), 3.25-3.16 (m, 1H), 3.51-3.43 (m, 1H), 4.29-4.22 (m, 1H), 7.08 (d, J=1.9 Hz, 1H), 7.62-7.50 (m, 5H), 7.72-7.66 (m, 1H), 7.97-7.86 (m, 3H), 9.19 (s, 1H). MS (ESI+) m/z 472.2 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[ClH:13]>O.[Pd]>[ClH:13].[NH:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=[O:11])[CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C(O)C1CCc2[nH]cnc2C1

Procedure:
A solution of benzimidazole-5-carboxylic acid (10 g, 62 mmol) in 1 N HCl (70 ml) and H2O (30 ml) was hydrogenated at 100 bar and 80° C. in the presence of 10% palladium on carbon (2.5 g) for 2 days. The mixture was filtered and the solvent was evaporated. The residue was stirred with acetone (100 ml) and the solid was isolated and dried. This afforded 10.6 g (79%) of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid hydrochloride.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[CH:15]1([SH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH:15]1([S:21][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: SC1CCCCC1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC(=O)c2cc(SC3CCCCC3)ccc21
Yield: 114.7 %

Procedure:
A mixture of 5-nitro-isoindole-1,3-dione (10.0 g), cyclohexanethiol (9.1 g) and potassium carbonate (18.7 g) in acetone (260 ml) was heated to reflux overnight. After cooling, the mixture was diluted with water (250 ml) and then acidified by 6 N HCl to pH=4. Precipitate was collected and dried in vacuo to give the intermediate 5-cyclohexylsulfanyl-isoindole-1,3-dione (15.6 g). This intermediate was dissolved in acetone (170 ml) and to the mixture was added bromo ethylacetate (10.6 g) and potassium carbonate (23.8 g). The mixture was refluxed overnight. After cooling, reaction mixture was filtered and rinsed with ethyl acetate. Filtrate was concentrated and purified by silica gel chromatography (10%-50% ethyl acetate in methylene chloride) to give the title compound (13.1 g). 1H NMR (200 MHz, CDCl3) δ 7.73 (m, 2 H), 7.56 (dd, J=7.8, 1.6 Hz, 1H), 4.40 (s, 2 H), 4.21 (q, J=7.0 Hz, 2 H), 3.37 (m, 1H), 2.07-1.28 (m, 13 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[N:11]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:13]([C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:14])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NCc1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
To a solution of (3-chloropyrazin-2-yl)methanamine.HCl (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21.26 mmol) in dichloromethane (250 mL) was added triethylamine (11.85 mL, 85 mmol) and the reaction mixture was cooled to 0° C. After 15 min stirring at 0° C., HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0° C. and then overnight at room temperature. The mixture was washed with 0.1 M HCl-solution, 5% NaHCO3, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate=1/4 v/v %) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%).
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:26])[C:23]([OH:25])=[O:24])=[C:17]([Cl:27])[CH:16]=2)=[CH:6][CH:5]=1.Cl>CN(C=O)C>[C:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:1][CH3:2])[C:23]([OH:25])=[O:24])=[C:17]([Cl:27])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)C(O)Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1Cl
Reactant: CCI
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1Cl)C(=O)O
Temperature: 50 °C

Procedure:
Ethyl iodide (0.6 mmol, 0.05 mL) was added to a solution of 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-hydroxy-propionic acid (Step A) and Ag2O (0.09 mmol, 21 mg) in DMF (0.5 mL). The mixture was heated at 50° C. for 24 hours. The mixture was warmed to room temperature, and 1N HCl was added until pH 3. The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated. The crude was purified by chromatography on silica gel (CH2Cl2) to afford the title compound. 1H-NMR (CDCl3, 300.15 MHz): δ 7.56–7.51 (m, 4H), 7.44–7.39 (m, 2H), 7.30 (t, 1H, J=7.3), 7.20 (d, 1H, J=8.5), 6.99 (d, 2H, J=8.7), 6.95 (d, 1H, J=2.4), 6.77 (dd, 1H, J=8.5, 2.4), 4.21–4.13 (m, 5H), 3.64–3.54 (m, 1H), 3.44–3.34 (m, 1H), 3.29 (dd, 1H, J=14.1, 4.2), 3.01 (dd, 1H, J=14.1, 8.7), 2.28 (qn, 2H, J=6.0), 1.12 (t, 3H, J=6.9).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Br-:9].[Br-].O1CCOCC1>CCOCC>[Br:9][C:6]1[CH:5]=[C:3]([OH:4])[C:1](=[CH:8][CH:7]=1)[OH:2]
Reactant: [Br-]
Reactant: Oc1ccccc1O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Oc1ccc(Br)cc1O

Procedure:
Catechol (11.0 g; 0.100 mol) is dissolved in 50 ml of ether and 29 g of freshly-prepared dioxane dibromide (Yanovskaya, Terent'ev and Belsn'kii), J. Gen. Chem. Vol. 22:1594 (1952)) is added slowly as a solution in 50 ml of ether. The organic solution is washed with water (3 times) and dried over MgSO4. The solvent is removed under reduced pressure to yield 4-bromocatechol as a red-brown oil. 1H NMR δ 5.52 (s, 1), 5.70 (s, 1), 6.74 (d, 1, J=8.74 Hz), 6.92 (dd, 1, J=8.3, 2.3 Hz), and 7.01 ppm (d, 1, J=2.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:11][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([OH:10])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c(C)c1O
Reaction time: 5 h

Procedure:
10 g (71 mmol) of 2,3,6-trimethylphenol are initially introduced in a solvent mixture consisting of 250 ml of dichloromethane and 190 ml of methanol, and 35.4 g (72 mmol) of tetrabutylammonium tribromide in 170 ml of dichloromethane and 130 ml of methanol are added. After 5 h at room temperature, the batch is evaporated in a rotary evaporator, and the residue remaining is taken up in MTB. The organic solution is washed three times with water, dried over sodium sulfate and evaporated in a rotary evaporator. The crystalline residue obtained is employed in the next step without further work-up.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:31][CH:30]=1)[NH:24][CH2:23][CH2:22]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C1COCC1>[C:1]1([S:7]([N:24]2[CH2:23][CH2:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:20]=3)[CH:25]2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:31][CH:30]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 168 %

Procedure:
Benzenesulfonyl chloride (0.016 g, 0.09 mmol) was added to a solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.040 g, 0.09 mmol) and Et3N (0.026 ml, 0.19 mmol) in anhydrous THF (10 ml) at rt under N2. The resulting suspension was stirred at rt for 18 hr, then evaporated in vacuo to give 0.086 g of yellow residue. Purification by flash chromatography, eluting with EtOAc:MeOH (6:4) gave 0.045 g (85% yield) of white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>ClCCl.CN(C1C=CN=CC=1)C>[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:38])([O-:33])=[O:32]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc([N+](=O)[O-])c3)ccc21
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (250 mg, 809 μmol) in dichloromethane (15 mL) was added triethylamine (280 μL, 2.03 mmol), 3-nitrobenzoyl chloride (375 mg, 2.03 mmol) and DMAP (10 mg, 81 μmol). The solution was stirred at room temperature for 144 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.53 min, MH+ 459].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:22]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccncc3)CC1)O2

Procedure:
Compound 57 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, isonicotinoyl chloride and conditions outlined in procedure N. M.p.=267-269° C.; 400 MHz 1H NMR (CDCl3) δ 8.73 (d, J=6 Hz, 2H), 8.08 (d, J=8 Hz, 1H), 7.75 (m, 1H), 7.70 (m, 1H), 7.66 (t, 1H), 7.52 (t, J=7.6 Hz, 2H), 4.68 (d, J=12 Hz, 1H), 3.63 (m, 1H), 3.50 (m 1H), 3.37 (m, 1H), 2.98 (d, 7.6 Hz, 2H), 2.28 (brm, 1H), 2.14 (brm, 1H), 1.91 (brm, 1H), 1.73 (brm, 1H); LCMS: 407 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:19]1[C:9]2[C:10](=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:7][CH:8]=2)[N:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=CNc1cc[nH]c1C(=O)OCC)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(C(=O)OCC)[nH]cc2c1Cl
Temperature: 75 °C

Procedure:
Diethyl 2-((2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)methylene)malonate was dissolved in phosphoryl chloride (0.2 M) and heated at 75° C. for 18 hours. Reaction mixture was concentrated to dryness and water and ethyl acetate were added. The aqueous layer was extracted with ethylacetate, the combined organic fractions were washed with brine and dried over magnesium sulfate before concentrating in vacuo to afford the crude compound 10a as an orange solid.
Reaction SMILES: Br[C:2]1([F:20])[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].O>COCCOC>[F:20][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1Cc2ccccc2C1)C1=CCC(F)(Br)C=C1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(NC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2C1)c1ccc(F)cc1
Yield: 44.5 %

Procedure:
150 mg (0.45 mmoles) 4-bromo-N-indan-2-yl-4-fluoro-benzamide, 102 mg (0.54 mmoles 3-trifluoromethylbenzeneboronic acid, 211 mg (0.67 mmoles) barium hydroxide octahydrate and 20 mg tetrakis-triphenylphosphine-palladium were suspended in 10 ml 1,2-dimethoxyethane and 10 ml water and heated to reflux for 7 h. Subsequently, the reaction mixture was evaporated to dryness, the residue taken up in methylenchloride and extracted twice with water. The oil remaining after evaporation of the organic phase was purified using prep. HPLC chromatography. (RP18, acetonitrile/water, 1% trifluoroacetic acid). 80 mg (45%) of the title compound were obtained.
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:31])[CH:10]([N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([CH3:31])[CH:10]([N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:11]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)NC(=O)OC(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)N)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of diethyl 1-{3-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (6.00 g, 13.8 mmol) in CH2Cl2 (20 mL) is added TFA (10 mL). The mixture is stirred at room temperature for 16 h. The mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The resulting white solid was collected by filtration and dried in vacuo to afford the title compound (3.83 g, 83%). LCMS: 334.80 (M+H+).
Reaction SMILES: [Na:1].CC1(C)O[C@H](C[O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[O:18])[C:11]=2[CH3:28])CO1.[CH3:30][C:31]1([CH3:43])[CH2:36][O:35][C:34]2([CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]2)[O:33][CH2:32]1>>[Na:1].[CH3:30][C:31]1([CH3:43])[CH2:32][O:33][C:34]2([CH2:37][CH2:38][CH:39]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)=[O:18])[C:11]=3[CH3:28])[CH2:40][CH2:41]2)[O:35][CH2:36]1
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Agent: [Na]
Product: Cc1c(OC2CCC3(CC2)OCC(C)(C)CO3)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (14a) to (14e) of Example 14 was repeated using the 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol obtained in the step (81a) above to obtain the title compound (275 mg, the total yield of 5 steps: 3.3%) as a white solid. Note that in the same process as in the step (14b), after acetic anhydride was added, 10 equivalents of triethylamine relative to pyridine1-oxide derivative was added to perform the reaction. In the same process as in the step (14c), tetrahydrofuran was used as a solvent instead of ethanol.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([O:27]C)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>CCCCCCC>[C:22]([O:24][CH:25]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:27]
Reactant: COC(=O)CCCCCCCCC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CCCCCCC
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To a 300 ml three-necked flask fitted with a stirrer, nitrogen inlet, thermometer, condenser and Dean-Stark trap is added 34.45 g (0.2 mol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 23.0 g (0.1 mol) of dimethyl sebacate and 110 ml of heptane. The reaction mixture is heated to reflux to dry the contents of the flask and 15 ml of slightly turbid distillate is removed from the Dean-Stark trap. The mixture is cooled to about 75° C. and 0.5 g of tetraisopropyl orthotitanate and 15 ml of heptane is added to the flask. The mixture is heated to reflux and heating at reflux temperature 100°-105° C. is continued for 24 hours with methanol being collected in the Dean-Stark trap. Water (5 ml) is added and heating is continued till all or most of the water is removed. The reaction mixture is allowed to cool slightly, is filtered and washed with heptane. Orange crystals form on standing and are collected by filtration, and washed with heptane. The orange crystalline product melts at 99°-101° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C.Cl>[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH2:11])=[CH:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 4-hydroxybenzenesulfonamide (1.73 g, 10.0 mmol) and tert-butyl(6-bromohexyl)carbamate (2.1 g, 7.5 mmol) in acetonitrile (50 mL) was added anhydrous K2CO3 (2.07 g, 15 mmol). The reaction mixtures were stirred at 75° C. for overnight. Solvent was evaporated under reduced pressure to give a residue. The residue was diluted with 1 N HCl (40 mL), extracted with DCM, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with DCM to 10% MeOH in DCM to afford tert-butyl(6-(4-sulfamoylphenoxy)hexyl)carbamate (1.192 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[CH:22]1([CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[CH2:31][NH2:32])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:32][CH2:31][C@H:27]2[CH2:28][CH2:29][CH2:30][N:26]2[CH2:25][CH:22]2[CH2:24][CH2:23]2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: NC[C@H]1CCCN1CC1CC1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate [see preparation 17] and [(2R)-1-(cyclopropylmethyl)pyrrolidinyl]methylamine [see WO 9839295 A1], to afford the product as a orange oil (100%). LRMS: m/z=445 (MH+).
Reaction SMILES: [Na].[CH3:2][CH:3]([C:5](C)([OH:23])[CH:6]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:4].[CH3:25]O>>[CH3:25][C:3]([CH3:2])([CH:5]([OH:23])[CH:6]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:4]
Reactant: CO
Reactant: CC(C)C(C)(O)C(CCCCOc1ccccc1)n1cncn1
Agent: [Na]
Product: CC(C)(C)C(O)C(CCCCOc1ccccc1)n1cncn1

Procedure:
72 g of solid sodium borohydried are added, a little at a time, to a stirred solution of 600 g of 2,3-dimethyl-4-(1,2,4-triazol-1-yl)-8-phenoxy-octan-3-ol in 1,000 ml of methanol; during the addition, the mixture reaches the refluxing temperature. When the exothermic reaction has subsided, the mixture is evaporated to dryness under reduced pressure. 500 ml of water are added to the residue and the batch is extracted three times with 300 ml of methylene chloride at a time. The combined organic phases are dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. 200 ml of diisopropyl ether are added to the residue, and 360 g of colorless crystals, of melting point 79°-81° C., are isolated from this mixture.