Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: SC1C=CC=C[N+]=1[O-].[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)C(Cl)=O)(=[O:11])[CH3:10].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:38]C(Cl)(Cl)Cl>>[C:9]([O:12][C:13]1[CH:14]=[C:15]([Br:38])[CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)(=[O:11])[CH3:10]
Reactant: ClC(Cl)(Cl)Br
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [O-][n+]1ccccc1S
Product: CC(=O)Oc1cc(Br)cc(OC(C)=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
2.6 g (17.5 mmol) 2-mercaptopyridine-1-oxid was dissolved in 30.0 ml bromotrichloromethane and heated to reflux. A mixture of 4.04 g (15 mmol) 3,5-diacetoxybenzoylchloride and 433 mg (2.5 mmol) 2,2′-azobisisobutyronitril dissolved in 30.0 ml bromotrichlioromethane were added dropwise at the same temperature. After additional 2 hours of refluxing the reaction mixture was cooled to room temperature and concentrated in vacuum. Chromatographic purification over silica gel employing a 9:1 (v/v) mixture of n-hexane and ethyl acetate as eluting agent yielded 2.4 g of 3,5-diacetoxybromobenzene (8.7 mmol, 58%).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([O:33][CH2:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([O:33][CH2:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC3CCCC3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(OCC3CCCC3)cc(-c3ccsc3)c2)c1CCC(=O)O
Yield: 100.5 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(3-cyclopentylmethoxy-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (117 mg, 0.17 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(3-cyclopentylmethoxy-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid (104 mg, 98%) as a off-white waxy solid: ES(+)-HRMS m/e calcd for C35H44O7S (M+H)+ 609.2881. found 609.2881.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2]>C(O)C.O.[C].[Pd]>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(=O)NC1CCNC1
Yield: 97.9 %

Procedure:
To a solution of the above 3-acetylamino-1-benzylpyrrolidine (4.0 g) in ethanol (30 ml) was added 10% palladium-carbon (0.8 g) in water (1 ml). The mixture was shaken at room temperature for 22 hours under hydrogen pressure of 55 p.s.i. using Parr hydrogenator. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and dried over anhydrous magnesium sulfate, followed by distilling off the solvent to give 3-acetylaminopyrrolidine (2.3 g) as oil.
Reaction SMILES: [N+:1]([C:4]1[C:23]([N+:24]([O-])=O)=[C:22]([O:27][CH3:28])[CH:21]=[CH:20][C:5]=1/[CH:6]=[CH:7]\[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CC(C)=O.O>[NH2:1][C:4]1[C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=[CH:20][C:5]=1/[CH:6]=[CH:7]\[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: COc1cc(/C=C\c2ccc(OC)c([N+](=O)[O-])c2[N+](=O)[O-])cc(OC)c1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(N)c1N
Temperature: 50 °C

Procedure:
A well-stirred solution of 2′,3′-Dinitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (0.422 g, 1.08 mmol) in a mixture of acetone-water (2:1) was heated to 50° C. Then sodium thiosulfate (1.88 g, 10.81 mmol, 10.0 equiv) was added and the reaction mixture was heated to reflux for 6 hours. The reaction was cooled to room temperature and water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (4×25 mL). The combined organic layer were washed with brine, dried over Na2SO4 and concentrated in vacuo. The mixture was then subjected to preparative TLC to give the 2′,3′-Diamino-3,4,4′,5-tetramethoxy-(Z)-stilbene.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([CH3:25])([CH3:26])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CC(C)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2,2-dimethyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (76%). MS: m/e=604(M+H+).
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)N.Br>CCCCCCC>[NH2:1][CH:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: NC(N)(c1cccnc1)C1CCOCC1
Agent: Br
Solvent: CCCCCCC
Product: NC(c1cccnc1)C1CCOCC1

Procedure:
2.1.]heptane: Treatment of 1-amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methaneamine (576 mg, 3 mmol) with hydrobromic acid, as described for the synthesis of the 1-aza-2-(3-pyridyl)bicyclo[2.2.1]heptanes resulted in formation of the product, as a dark brown oil which was purified by column chromatography (15% methanol in chloroform), followed by distillation (90° C. at 0.005 mm Hg) under reduced pressure to obtain the product as a colorless oil (260 mg, 51% from 1-amino-1-(3 -pyridyl)-1-(4-tetrahydropyranyl)-methane.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)N>>[CH2:26]([O:25][C:24]1[CH:23]=[CH:22][C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)=[CH:19][C:18]=1[CH3:17])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Cc1cc(N)ccc1OCc1ccccc1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccc1
Yield: 64.2 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (2.0 g, 8.96 mmol) and 3-methyl-4-benzyloxyaniline (2.1 g, 9.87 mmol) to give the title compound as a white solid (2.25 g, 64%); NMR Spectrum: 2.23 (s, 3H), 3.79 (t, 2H), 4.30 (t, 2H), 5.15 (s, 2H), 7.03 (d, 1H), 7.32-7.48 (m, 7H), 8.21 (s, 1H), 8.33 (s, 1H); Mass Spectrum: 392 (MH+).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]2[C:18]3[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[Cl:26])=[CH:4][C:3]=1[F:29].[F:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][C:18]2[C:8]([S:7][CH2:6][C:5]3[CH:27]=[CH:28][C:2]([C:33]4[CH:32]=[C:31]([F:30])[CH:36]=[CH:35][C:34]=4[O:40][CH3:41])=[C:3]([F:29])[CH:4]=3)=[C:9]([Cl:26])[CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)c(F)c3)c2CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 100 °C
Yield: 93.3 %

Procedure:
Degas a stirred mixture of 6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (212 mg, 0.424 mmol), 5-fluoro-2-methoxybenzene boronic acid (108 mg, 0.636 mmol), potassium carbonate (292 mg, 2.12 mmol), triphenylphosphine (11 mg, 0.0424 mmol) and bis(triphenylphosphine)-palladium(II) chloride (15 mg, 0.0212 mmol) in dioxane (3 mL) and water (1 mL). Purge with dry nitrogen and heat at 100° C. for 5 h. Cool to ambient temperature, add water, extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2,5′-difluoro-2′-methoxy-biphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as yellow oil (216 mg, 93%). Use a method similar to the General Procedure 1-4 to give the title compound as a yellow foam. MS (ES+) m/z: 446 (M+H)+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]1[O:54][C:53](=[O:55])[NH:52][CH2:51]1)[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]4[O:54][C:53](=[O:55])[NH:52][CH2:51]4)([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C5CNC(=O)O5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C5CNC(=O)O5)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a solution of 5-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]oxazolidin-2-one 27a (113 mg, 0.17 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.1 mL, 0.85 mmol) and 10% Pd/C (20 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filter cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 27 as a white solid (66.2 mg, 78.8%, HPLC: 90.1%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 492.2 [M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.54 (s, 1H), 7.42 (m, 2H), 7.31 (m, 1H), 7.16 (m, 2H), 7.34 (m, 2H), 5.68 (d, 1H), 5.18 (d, 2H), 4.81 (t, 1H), 4.11 (m, 1H), 3.98 (m, 4H), 3.69 (t, 1H), 3.48 (m, 3H), 3.30 (m, 1H), 3.21 (m, 1H), 1.32 (t, 3H).
Reaction SMILES: C(O)(C)C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([N+:23]([O-])=O)=[C:15]([C:26]([F:29])([F:28])[F:27])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C:26]([F:27])([F:28])[F:29])[C:16]([NH2:23])=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
Isopropanol (450 mL) was added to 4-benzyloxy-2,6-bis(trifluoromethyl)nitrobenzene (9.00 g, 24.6 mmol) and the latter was dissolved in the former by heating at 70° C. A solution of sodium dithionite (14.1 g, 81.2 mmol) in water (150 mL) was added dropwise to the resulting solution. After stirring for 30 minutes at the same temperature, a solution of sodium dithionite (7.28 g, 41.8 mmol) in water (150 mL) was added further. The reaction mixture was stirred at the same temperature for 14 hours and then, the isopropanol was distilled off under reduced pressure. Ethyl acetate was added to the resulting suspension to separate it into layers. The aqueous layer was extracted with ethyl acetate twice. The organic layers were combined, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent, whereby 8.26 g (yield: 100%) of 4-benzyloxy-2,6-bis(trifluoromethyl)aniline was obtained as colorless needle-like crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:22])[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15].C(N(CC)CC)C>CN(C)C=O>[NH2:8][C:6]1[N:7]=[C:2]([N:18]2[CH2:19][CH2:20][CH2:21][C@@H:16]([C:14]([N:13]([CH3:22])[CH3:12])=[O:15])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C(=O)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (4.15 g, 24.0 mmol) in N,N-dimethylformamide (41 mL) was added (R)—N,N-dimethylpiperidine-3-carboxamide (3.74 g, 2.40 mmol) followed by triethylamine (10.7 mL, 64.800 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via column chromatography to afford (R)-1-(6-amino-5-nitropyridin-2-yl)-N,N-dimethylpiperidine-3-carboxamide.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[Cl:26][C:27]1[S:28][C:29]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:35])=[O:34])=[CH:30][C:31]=1[NH2:32]>>[Cl:26][C:27]1[S:28][C:29]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:34])=[O:35])=[CH:30][C:31]=1[NH:32][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: CN1CCN(S(=O)(=O)c2cc(N)c(Cl)s2)CC1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN1CCN(S(=O)(=O)c2cc(NC(=O)c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)c(Cl)s2)CC1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-ylamine (example B.22) according to general procedure II.
Reaction SMILES: C([CH:5]([OH:35])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:26]3[C:14]([C:15]([N:17]=[C:18]([N:25]=3)[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:16])=[N:13][C:12]2=[SiH2])[C@H:8]([O:28][CH3:29])[C@@H:7]1[O:30]C(C)(C)C)(C)(C)C.N1C=CC=CC=1.N1C=CC=CC=1.F>ClCCl>[CH3:29][O:28][C@@H:8]1[C@H:7]([OH:30])[C@@H:6]([CH2:5][OH:35])[O:10][C@H:9]1[N:11]1[C:26]2[N:25]=[C:18]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[NH:17][C:15](=[O:16])[C:14]=2[N:13]=[CH:12]1
Reactant: CO[C@@H]1[C@H](OC(C)(C)C)[C@@H](C(O)C(C)(C)C)O[C@H]1n1c(=[SiH2])nc2c1=NC(NC(=O)C(C)C)=NC2=O
Agent: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Yield: 93 %

Procedure:
To a stirred solution of (66) (0.51 g, 1 mmol) in anhydrous dichloromethane (5 ml) was added pyridine (0.5 ml) followed by hydrogen fluoride—pyridine (38.5 M, 0.1 ml). After 15 min the solvent was removed in vacuo. Flash chromatography using a gradient of 5-10% methanol in dichloromethane afforded (67) as white foam, 0.34 g, 93% yield.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[N:13]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[CH:16]=1.[Cl:39][CH2:40][C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)[CH:42]=1>>[ClH:39].[ClH:1].[ClH:39].[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[N:13]([CH:33]1[CH2:34][CH2:35][N:36]([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([C:47]3[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=3)[CH:42]=2)[CH2:37][CH2:38]1)[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[CH:16]=1
Reactant: COc1cc(-c2cc(CN(c3cccc(OC)c3OC)C3CCNCC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)c4cccc(OC)c4OC)CC3)ccn2)cc(OC)c1OC

Procedure:
4-[N-(2,3-Dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride (113 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (59 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as light yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]1[N:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH3:28])=[CH:20][N:19]=1>C1(C)C=CC=CC=1.CCO.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([O:26][CH2:25][O:24][C:21]1[CH:20]=[N:19][C:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:23][CH:22]=1)[CH3:28]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOCOc1cnc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCOc1cnc(-c2ccc(F)cc2)nc1
Temperature: 86 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
A stirred mixture of 4-fluorophenylboronic acid (282 mg, 2.02 mmol) and Pd(dppf)Cl2 (199 mg, 0.272 mmol) in toluene (14 mL) and EtOH (7 mL) was degassed for 10 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (3.3 mL, 6.6 mmol) was added by syringe and the stirred mixture was again degassed for 10 min, and then N2 was added, followed by chloropyrimidine 108 (260 mg, 1.38 mmol). The resulting mixture was stirred at 86° C. for 2.5 h, and then cooled, diluted with aqueous NaHCO3 (50 mL) and extracted with CH2Cl2 (5×50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% Et2O/petroleum ether firstly gave foreruns, and then further elution with 2% Et2O/petroleum ether gave 5-(ethoxymethoxy)-2-(4-fluorophenyl)pyrimidine (109) (312 mg, 91%) as a white solid: mp (petroleum ether) 42-44° C.; 1H NMR (CDCl3) δ 8.58 (s, 2H), 8.36 (ddt, J=9.0, 5.6, 2.5 Hz, 2H), 7.14 (tt, J=8.8, 2.5 Hz, 2H), 5.30 (s, 2H), 3.77 (q. J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); HRESIMS calcd for C13H13FN2O2 m/z [M+H]+ 249.1034. found 249.1039.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.CCN(C(C)C)C(C)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[C:18]([OH:36])(=[O:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 0 °C

Procedure:
1.33 gr. of N-hydroxy succinimide (11.56 mmole, 1.5 eq.) and DIEA (1.35 ml), were dissolved in 50.0 ml of anhydrous THF and gently stirred at 0° C. under nitrogen atmosphere. Then, Oleoyl chloride (3.0 ml, 85% tech., 7.8 mmole, 1.0 eq.) dissolved in 50 ml of anhydrous THF was added dropwise during 1 h. The mixture was gently stirred for 2 h at 0° C. and over-night at room temperature. The resulting precipitate were discarded by filtration and the filtrate was evaporated under reduced pressure, redissolved in small amount of DCM and purified over silica-gel column using DCM as eluent. Fractions containing the product were combined and solvent was removed under reduced pressure. The resulting white solid was dried in vacuum over NaOH-pellets.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:16])([O:6][C:7]([NH:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][OH:12])=[O:8])[CH3:5].I[CH3:18]>CN(C=O)C.Cl>[CH3:5][C:4]([CH3:16])([O:6][C:7]([NH:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][CH3:18])=[O:8])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
Sodium hydride (60% dispersion, 4.3 g, 0.107 mol) was added portionwise at 0° C. to a stirred solution of (S)-N-(1,1-dimethylethoxy)carbonylserine (10 g, 48.7 mmol) in anhydrous DMF (250 ml). A solution of iodomethane (6.1 ml, 0.1 mol) in anhydrous DMF (10 ml) was then added dropwise. The mixture was allowed to warm to RT and stirred overnight, then diluted with 1N hydrochloric acid to pH3 and the solution concentrated in vacuo to ca. 100 ml. The mixture was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried (MgSO4) and evaporated in vacuo to provide the title compound as a yellow oil (7.48 g, 70%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]([CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:38]=[CH:39][CH:40]=2)O1.C([O-])(=O)C.[K+]>C(#N)C.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:39]4[CH:38]=[C:37]([CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:36]=[CH:35][CH:40]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CS(C)=O
Product: COC(=O)Cc1cccc(-c2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)c1
Temperature: 80 °C

Procedure:
Following the procedure of Example 93, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150, methyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate, potassium acetate, and Pd(dppf)Cl2 in acetonitrile and DMSO were heated at 80° C. overnight to give 200. MS: (ESI+) 518.2