Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:20](C(O)=O)=[N:19][C:18]2[C:17]3[S:24][C:25](CC)=[CH:26][C:16]=3[CH2:15][CH2:14][O:13][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:29]1[CH2:33]CCC1.[OH-:34].[Li+]>O>[Si:1]([O:8][CH2:9][C:10]1[CH:20]=[N:19][C:18]2[C:17]3[S:24][C:25]([C:33]([OH:29])=[O:34])=[CH:26][C:16]=3[CH2:15][CH2:14][O:13][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CCc1cc2c(s1)-c1nc(C(=O)O)c(CO[Si](C)(C)C(C)(C)C)cc1OCC2
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnc2c(c1)OCCc1cc(C(=O)O)sc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-tert-butyldimethylsilyloxymethyl-9-ethylcarboxy-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (0.100 g, 0.238 mmol) in tetrahydrofuran (0.715 mL, 8.82 mmol) and water (0.715 mL, 39.7 mmol) was added 1.00 M of lithium hydroxide in water (0.715 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was acidified with 1M HCl then extracted with EtOAc (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 3-tert-butyldimethylsilyloxymethyl-9-carboxy-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine to which was added 5 ml DCM, triethylamine (0.166 mL, 1.19 mmol) and acetic anhydride (0.112 mL, 1.19 mmol). The reaction was stirred at room temperature 1 h. The reaction was quenched with NaHCO3 washed with EtOAc. The organic layer was acidified 1M HCl extracted EtOAc (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 3-acetoxymethyl-9-carboxy-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine which was dissolved in 5 ml DCM. A solution of 2.0 M oxalyl chloride in methylene chloride (DCM, 0.357 mL) and 1 drop of DMF was added. The reaction was stirred at room temperature 2 h. The reaction was concentrated to give 3-acetoxymethyl-9-chlorocarbonyl-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine which was dissolved in 5 ml acetonitrile. 3-Chloro-N,N-dimethyl-4-(methylamino)benzamide (0.101 g, 0.477 mmol;) and sodium bicarbonate (0.040 g, 0.47 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was quenched water, extracted three times with ethyl acetate, and concentrated. The crude product was purified by flash chromatography (50-100% EtOAc/Hex) (product eluted at 100% EtOAc, sm at 75% EtOAc) to give N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-N-methyl-(3-acetoxymethyl-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine)-9-carboxamide (41%). MS: (ESI+) 514.3
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+].[Cl-].[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH2:7]([O:20][CH2:19][CH:18]1[CH2:17][CH2:21][CH2:3][CH:2]=[CH:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Product: C1=CC(COCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A solution of potassium t-butoxide (1.0M in THF, 8.27 mL, 8.27 mmol) was added dropwise to a solution of (±)-3cyclohexane-1-methanol (853 mg, 7.60 mmol) in THF (35 mL) at 25° C. under N2. The resultant mixture was stirred at 25° C. for 30 minutes. Benzyl bromide (1.0 mL, 8.37 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 16 hours and then treated with saturated aqueous NH4Cl (5 mL) and concentrated. The residue was dissolved in ether (50 mL), washed with water (20 mL) and brine (20 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was subjected to radial chromatography on silica gel eluting with 5 percent EtOAc in hexane to give (±)-3-(benzyloxy)methyl-1-cyclohexene (1.42 g, 92 percent) as a colorless oil. NMR
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:15]=[CH:16][CH2:17][CH2:18][CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-(1-pentenyl)-6-methylpiperidine (2.5 g, 9.35 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-(1-pentenyl)-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid that was homogeneous by TLC analysis. mp 150.4-150.9° C.; 1H NMR (250 MHz) δ9.5-9.3 (br. d, 2H), 5.74-5.62 (m, 2H), 4.19 (s, 1H), 3.55 (s, 1H), 2.1-1.3 (m, 13H), 0.87 (t, 3H); 13C NMR (62.7 MHz) δ136.8 (s), 123.0 (s), 48.3 (s), 47.9 (s), 29.9 (s), 28.8 (s), 28.4 (s), 22.3 (s), 17.6 (s), 17.1 (s), 13.8 (s). FT-IR (neat): 3424, 3171, 2939, 1635, 1597, 1582, 1459, 1432, 1384, 1287, 1123, 1075, 895. Elemental Analysis for C11H22NCl: C, 64.83%; H, 10.9%; N, 6.87%. Found: C, 64.77%; H, 10.82%; N, 6.85%.
Reaction SMILES: [CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25][CH3:26])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25]([CH3:26])=[O:38])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CSCc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (0.22 mmol) of the compound from Example 94 were introduced into 6 ml of dichloromethane at 0° C., 56.1 mg (0.23 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. Methanol was added, and the residue after concentration was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 43.6 mg (52% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:16]([Si:20]([CH3:45])([CH3:44])[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1/[CH:32]=[C:33](/[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[F:43])\[C:34]#[N:35])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:32]([C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=2[O:24][CH2:23][CH2:22][O:21][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:45])[CH3:44])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[F:43])([C:34]#[N:35])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Cl)ccc2OCCO[Si](C)(C)C(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 18.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (3.7 g, 8 mmol) prepared in Example 84a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.0 g, 18%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>C1COCC1.O>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0° C. After stirring at 0-5° C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0° C. and benzenesulfonyl chloride (0.283 ml, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0-5° C. Excess sodium hydride was decomposed by the addition of methanol (0.4 ml) followed by water (0.5 ml). The solvent was removed under reduced pressure. The residue was dissolved in water (20 ml), basified to pH 8-9 by the addition of sodium hydroxide and extracted with ethyl acetate (2×10 ml) to remove the neutral impurities. The aqueous layer was acidified with concentrate HCI (pH 2-3) and extracted with ethyl acetate (3×10 ml) The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide. The pure material was obtained by recrystallization using hexanes/ethyl acetate (0.59 g, 93% yield), m.p. 142-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24]COC)=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:21]([O-:23])=[O:22])[CH:14]=[N:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:21]([O-:23])=[O:22])[CH:14]=[N:13][CH:12]=2)[C:4]=1[OH:24]
Reactant: COCOc1c(-c2cncc3cccc([N+](=O)[O-])c23)ccc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cncc3cccc([N+](=O)[O-])c23)c(O)c1OC
Reaction time: 4 h

Procedure:
After dissolving isoquinoline 4 (5.285 g, 0.014 mol) in 200 ml of methanol by gentle heating, p-toluenesulfonic acid monohydrate (8.15 g; 0.043 mol) was added in several portions. Stirring was continued for four hours at room temperature. After completion of the reaction, the solution was made basic by adding saturated sodium bicarbonate. The product was then extracted with dichlormethane (3×250 ml), dried (Na2SO4), and concentrated. The resulting yellow solid (4.65 g; 98%) was used directly in the next reaction. An analytical sample was recrystallized from methanol: mp 170-174° C.; 1H NMR: (300 MHz, CDCl3): 9.33 (s, 1H); 8.62 (s, 1H); 8.24 (dd, 1H, J=7.2, 0.9 Hz); 7.99 (dd, 1H, J=6.3, 1.2 Hz); 7.67 (t, 1H, J=7.8 Hz); 6.96 (d, 1H, J=8.7 Hz); 6.59 (d, 1H, J=8.7 Hz); 5.88 (bs, 1H); 3.94 (s, 3H); 3.92 (s, 3H). CIMS mn/z: 327 (M+H+, 100%). Anal Calc'd for C17H14N2O5: C, 62.57; H, 4.32; N, 8.58; Found: C, 62.18; H, 4.38; N, 8.35.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[S:8]([O-:11])([O-:10])=[O:9].[Na+].[Na+].[OH2:14]>>[S:8]([CH:2]([CH:3]([S:8]([OH:11])(=[O:10])=[O:9])[C:4]([OH:14])=[O:5])[C:1]([OH:6])=[O:7])([OH:11])(=[O:10])=[O:9]
Reactant: O
Reactant: O=C1C=CC(=O)O1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)C(C(C(=O)O)S(=O)(=O)O)S(=O)(=O)O

Procedure:
Under the conditions specified under (c) 50 parts of oxethylation product (b) are esterified with 10.6 parts of maleic anhydride, whereupon a solution of 13.7 parts of sodium sulfite (anhydrous) in 112 parts of water is added at 70° to 80° C. When the mixture has become clear, it is stirred for a further hour at the same temperature. The amount of water added can vary between 50 and 85% by weight of the final solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([NH:21][NH2:22])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[N:27]#[C:28]Br.[CH:30]([NH2:33])([CH3:32])[CH3:31]>CC(O)=O>[NH2:27][C:28]1[N:33]([CH:30]([CH3:32])[CH3:31])[C:19]([C:13]2[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]([F:26])([F:25])[F:24])[CH:4]=3)(=[O:10])=[O:9])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=2)=[N:21][N:22]=1
Reactant: N#CBr
Reactant: CC(C)N
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CC(C)n1c(N)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 35 mL scintillation vial was charged with 4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (500 mg, 1.1 mmol), cyanogenbromide (200 mg, 2.0 mmol) anhydrous MeCN (5 mL). The resultant mixture was heated to 65° C. and stirred for 2 h. After cooling to room temperature, isopropylamine (500 mg, 8.2 mmol) was added followed by AcOH (0.5 mL) and the mixture was heated to 135° C. and stirred for 2 h. After cooling to room temperature, reaction mixture was concentrated under reduced pressure. The residue was further purified through automated normal-phase chromatography (10% to 100% gradient of EtOAc-Hexane) and followed by preparative HPLC (10% to 90% gradient of MeCN-water) and dried (Lyophilizer) to afford the title compound. 1H NMR (400 MHz, CDCl3) 8.28 (d, 1H), 8.18 (d, 1H), 8.10 (d, 1H), 7.90 (dd, 1H), 7.58 (d. 1H), 4.32 (br, 1H), 3.88 (m, 1H), 1.34 (d (d, 6H). MS (ES) [M+H]+ expected 495.0, found 495.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[C:13]([Cl:32])=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=CC=2)[N:3]=1.[H-].[Na+].[C:35]([N:39]=[C:40]=[O:41])([CH3:38])([CH3:37])[CH3:36].[CH3:42][N:43](C=O)C>CCOC(C)=O>[C:35]([NH:39][C:40](=[O:41])[NH:1][C:2]1[C:11]([C:12]2[C:13]([Cl:32])=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:43][CH:42]=2)[N:3]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Nc1nc2ccccc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Reactant: CC(C)(C)N=C=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)Nc1nc2ccncc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[3-(2-amino-quinolin-3-yl)-2,4-dichloro-phenyl]-3-trifluoromethyl-benzamide (100.0 mg, 0.210 mmol) in DMF (4.0 mL) is added NaH (60%, 10.9 mg, 0.273 mmol) at room temperature. After the mixture is stirred for 30 minutes at room temperature, tert-butyl isocyanate (24.9 mg, 0.252 mmol) is added and the mixture is stirred 6 hours. The reaction mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N) (95/5) to give the final product as a solid: 1H NMR 400 MHz (CDCl3) δ 9.97 (s, 1H), 9.56 (s, 1H), 8.80 (m, 2H), 8.44 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 8.12 (d, 1H), 7.94 (m, 2H), 7.37 (t, 1H), 7.67 (d, 1H); MS m/z 577.70 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9](B(O)O)[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1.[Ag]=O>[Cl:1][C:2]1[C:3]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CB(O)O
Reactant: Clc1cccnc1I
Agent: O=[Ag]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1ncccc1Cl
Temperature: 75 °C
Yield: 52.9 %

Procedure:
3-Chloro-2-iodopyridine (1.552 g, 6.482 mmol), isobutylboronic acid (0.725 g, 7.112 mmol), potassium carbonate (2.7 g, 0.0195 mol) and silver oxide (3.8 g, 0.0164 mol) were suspended in THF (25 mL). The mixture was degassed three times and 1,1-Bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane (1:1) (0.520 g, 0.637 mmol) was added. The reaction mixture was heated at 75° C. under nitrogen for seven hours. The mixture was diluted EtOAc (15 mL) and washed with an aqueous solution of hydrochloric acid (2.0 M, 2×15 mL). The organic layer was discarded and the aqueous layer basified with careful addition of a saturated aqueous solution of sodium hydrogen carbonate (50 mL). The product was extracted with EtOAc (2×15 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 5% EtOAc in heptane to yield the title compound as a colourless oil (0.582 g, 53% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[C:4](=[O:24])[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:7](=[O:11])[C:6]=1[CH3:12])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (3.38 g) was dissolved in dichloromethane (50 ml). Pyridine (1 ml) was added, and acetyl chloride (0.8 ml) was added with stirring under ice-cooling. After stirring for 1 hour at the same temperature, the mixture was washed with 0.1N hydrochloric acid (50 ml) followed by water (50 ml). The dichloromethane layer was concentrated under reduced pressure to obtain 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methyl-l,4-benzoquinone as a red oil. This oil was dissolved in ether (50 ml), and a solution of sodium hydrosulfite (4 g) in water (50 ml) was added. Stirring was continued at room temperature until the red color of the ether layer disappeared. The ether layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound (3.8 g) as a pale yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC(F)(F)F)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2,2,2-trifluoroethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(O)C[OH:30].O.C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([O:25][CH2:26][CH2:27][OH:30])=[O:24]
Reactant: OCCO
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)OCCO
Reaction time: 50 h

Procedure:
A mixture of ethyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (2 g) and ethyleneglycol (8 ml) was stirred for 50 hours at 90°. The reaction mixture was poured into a mixture of water (50 ml), ethyl acetate (50 ml) and tetrahydrofuran (50 ml). The solvent was distilled off. The residue was chromatographed on silica gel, eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the object compound were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford 2-hydroxyethyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([OH:18])[CH:9]=1.I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>CN(C=O)C>[CH2:20]([O:18][C:10]1[CH:9]=[C:8]([I:7])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCI
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1cc(I)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.8 %

Procedure:
A suspension of caesium carbonate (35.2 g, 108 mmol), methyl 4-iodo-2-hydroxybenzoate (25 g, 90 mmol), iodoheptane (19.2 ml, 117 mmol) in DMF (500 ml) is stirred for 10 hours at room temperature. The organic phase is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. After evaporation of the remainder of the iodoheptane by placing the oil obtained under vacuum produced by a rotary vane pump, 33.8 g (100%) of the expected compound are recovered in the form of a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C@H:13]2[C@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14]2)=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:19]2[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14][C@H:13]2[CH2:12][NH:11][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:37][N:36]=[N:35][N:2]=3)[CH:4]=2)=[O:10])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cccc(C#N)c2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cccc(-c3nnn[nH]3)c2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(3-cyanophenyl)carbonyl]amino}methyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in DMF (4 mL) were added sodium azide (38.7 mg) and ammonium chloride (37.1 mg) at room temperature, and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (32 mg).