Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])(C(OCC)=O)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCCC(=O)O)N=C2c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (6 g) is dissolved in diethyl carbonate (100 ml) under a nitrogen stream, and 60% sodium hydride (1.2 g) is added with stirring at room temperature. The mixture is refluxed under heating for 1 hour and cooled to 50° C. with ice water. Ethyl bromobutyrate (4.3 ml) is added. After stirring at 100° C. for 2 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) and crystallized from isopropyl ether to give 3.9 g of (±)-ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyrate as white powdery crystals. (±)-Ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)butyrate (3.5 g) is dissolved in a mixture of ethanol (180 ml) and water (60 ml), and barium hydroxide 8 hydrate (8.4 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 1N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate to give 1.1 g of (±)-4-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyric acid as white powdery crystals, melting point 185°-187° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:26])=O.[NH2:27][C:28]([NH2:30])=[S:29]>CCO>[CH3:11][C:10]1[CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)[CH:7]=[C:6]([CH3:26])[C:5]=1[C:3]1[N:27]=[C:28]([NH2:30])[S:29][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1-c1csc(N)n1
Yield: 100.3 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)ethanone (26-3, 9.53 g, 23.2 mmol) and thiourea (1.76 g, 23.1 mmol) in 95% EtOH (33.1 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and washed with ethyl acetate. The solids were dried under vacuum to give 4-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)thiazol-2-amine (26-4, 9.00 g) as brown solids in 100% yield, which was used directly for the next step without further purification.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[Br:19])[CH:8]=[N:7][CH:6]=1.[Cl-].CC([O-])(C)C.[K+]>>[Br:19][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:11]=1[CH:10]1[N:9]2[CH:8]=[N:7][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2]1)[C:15]#[N:16]
Reactant: N#Cc1ccc(Cn2cncc2CCCO)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1

Procedure:
4-{5-[3-Hydroxypropyl]imidazol-1-ylmethyl}-3-bromobenzonitrile is converted to the corresponding chloride according to Example 14B. The resulting chloride is treated with a base, such as t-BuOK as in Example 14C above, to effect cyclization to the title compound. MS (ESI) m/z 302.1, 304.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.74-1.85 (m, 2 H), 2.08-2.17 (m, 1 H), 2.34-2.43 (m, 1 H), 2.82-2.91 (m, 1 H), 2.93-3.00 (m, 1 H), 5.88 (t, J=5.6 Hz, 1 H), 6.75 (d, J=8.1 Hz, 1 H), 6.82 (d, J=1.0 Hz, 1 H), 7.34 (s, 1 H), 7.69 (dd, J=8.1, 1.5 Hz, 1 H), 8.09 (d, J=1.5 Hz, 1 H).
Reaction SMILES: [N:1]1([CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19]C)=[O:17])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.ClC(Cl)(Cl)C([N:38]=C=O)=O.[N-]=C=O.C[O-].[Na+]>>[NH2:38][C:5]1[C:4]2[N:3]=[CH:2][N:1]([CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH3:19])=[O:17])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CCOC(=O)C(C)(C)Cn1cnc2cnc3ccccc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [N-]=C=O
Product: COC(=O)C(C)(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A modification of the methods described in Part B of Example 60 was used to treat ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (4.3 g, 14 mmol) with mCPBA (6.3 g of 77% pure material), followed by trichloroacetyl isocyanate (2.0 mL, 17 mmol). The reaction with the isocyanate was stirred for two hours before the addition of additional trichloroacetyl isocyanate (1.0 mL) and stirring for an additional two hours. After the reaction with sodium methoxide (11 mL of 25% in methanol), the solvent was removed under reduced pressure. The residue was mixed with methanol (25 mL), and the mixture was cooled to 0° C. and filtered to isolate 1.61 g of methyl 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as a solid. The filtrate was concentrated under reduced pressure, and the residue was mixed with saturated aqueous sodium bicarbonate (100 mL). A precipitate formed, was isolated by filtration, and was mixed with concentrated hydrochloric acid to adjust to pH 7. The precipitate was again isolated by filtration and dissolved in dichloromethane. The resulting solution was dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide an additional 1.51 g of methyl 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19](=[O:20])[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:29][CH2:28]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 71 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-(N-BOC-amino)-piperidine using standard reductive amination conditions. The resulting crude oil was triturated with diethyl ether and methanol to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a solid (71% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 340 as an off white solid (18% yield). NMR (CDCl3, 400 MHz), 1.43-1.48 (2H, m), 1.84 (2H, d, J=10.3), 2.19 (2H, t, J=11.3), 2.70-2.73 (1H, m), 2.93-2.96 (2H, m), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=427
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[Cl:11][C:12]1[C:13]([O:22][C:23]2[C:27]([CH2:28][CH3:29])=[C:26]([CH3:30])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:25]1[C:26]([CH3:30])=[C:27]([CH2:28][CH3:29])[C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[O:10]
Reactant: CN=C=O
Reactant: CCc1c(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(Oc2ncc(C(F)(F)F)cc2Cl)nn(C(=O)NC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Potassium carbonate (0.83 g, 6.0 mmol) and methyl isocyanate (0.29 g, 5.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole (1.83 g, 6.0 mmol) in ethyl acetate (25 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole-1-carboxamide (1.14 g, yield: 62.9%). mp: 84-86° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.04 (t, J=7.6 Hz, 3H), 2.26 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 2.93 (d, J=5.0 Hz, 3H), 6.80-7.05 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:9][C@H:8]2[C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.O.Cl>[N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccncc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl trans-2-pyridin-4-ylcyclopropanecarboxylate (0.918 g, 4.80 mmol) in THF (10 mL) and water (10 mL) was added lithium hydroxide (0.345 g, 14.4 mmol). The reaction mixture was allowed to stir at rt for 24 h and then diluted with 2N HCl (10 mL). The mixture was concentrated to give trans-2-pyridin-4-ylcyclopropanecarboxylic acid which was used without purification in the next step. LCMS: (FA) ES+ 164.0, ES-162.1.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([N:38]([CH3:40])[CH3:39])[CH:36]=5)[C:31]([CH3:41])=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:43].O1CCOCC1>O1CCOCC1>[ClH:43].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([N:38]([CH3:39])[CH3:40])[CH:36]=5)[C:31]([CH3:41])=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(N(C)C)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(N(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.12 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The solvent was removed under reduced pressure, the resulting solid was recrystallized in methanol-ethyl acetate to give 44 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-dimethylamino-4-methylquinolin-2(1H)-one hydrochloride as a brown solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.CCCCCC>C1COCC1>[CH2:14]([O:13][C:11]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[C:4]([CH2:3][OH:2])[CH:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(C(=O)O)cc(C(=O)OC)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
A solution of 5-Butoxy-isophthalic acid monomethyl ester (1.0 g, 4.0 mmol) in THF (20 mL) is treated with 2.0 M borane-dimethyl sulfide complex in hexane (10 mL, 20 mmol). The mixture is stirred at room temperature for 48 h. The mixture is quenched carefully with methanol (10 mL) and is concentrated to dryness. The residue is purified by flash chromatography to afford the title compound as a solid (0.78 g, 88%). LC-ES/MS m/e 211.3 (M+1).
Reaction SMILES: C([N:8]1[C:12]2[N:13]=[C:14]([NH:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[N:15]=[C:16]([S:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[CH3:26][C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[C:23]([CH3:24])[C:18]=1[S:17][C:16]1[C:11]2[CH:10]=[CH:9][NH:8][C:12]=2[N:13]=[C:14]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=2)[N:15]=1
Reactant: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3[nH]ccc23)c(C)c1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 34.6 %

Procedure:
To a solution of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (103 mg, 0.21 mmol) in 1,2-dichlorobenzene (2 mL) was added aluminum chloride (87 mg, 0.65 mmol). The reaction mixture was stirred at 160° C. for 1.5 h and cooled to room temperature. The mixture was poured into ice water and extracted with CH2Cl2 (2×10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=50:50) yielded 28 mg (34%) of 4-[4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Reactant: O=C(O)c1ccc(F)cn1
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ccc(F)cn2)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=379.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32]([CH3:40])[CH:31]=1)=[O:28].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][N:8]2[CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=[C:32]([CH3:40])[CH:31]=2)=[O:28])=[CH:21][CH:22]=1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(F)cc1)NCC2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(F)cc1)N(CCNC(=O)Nc1cc(C)nc3ccccc13)CC2
Temperature: 75 °C
Reaction time: 120 h

Procedure:
To a solution of 1-(4-fluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (example A1, 50 mg, 0.16 mmol) in anhydrous THF (2.5 mL) is added 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (example D1, 43.8 mg, 0.16 mmol), TEA (34.6 μL, 0.25 mmol) and Nal (2.5 mg, 0.017 mmol). The mixture is stirred at 75° C. for five days in a sealed flask. The reaction mixture is evaporated, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])[CH:17]=O.S(=O)(=O)(O)O.[CH3:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[CH3:48])[CH:32]=[C:33]([C@@H:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43][OH:44])[OH:42])[OH:40])[OH:38])[OH:36])[OH:34]>>[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])[CH:17]=[C:43]([OH:44])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@@H:35]([OH:36])[C:33](=[CH:32][C:31]1[CH:45]=[CH:46][C:47]([CH3:48])=[C:29]([CH3:28])[CH:30]=1)[OH:34]
Reactant: Cc1ccc(C=O)cc1C
Reactant: Cc1ccc(C=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1C
Agent: O=S(=O)(O)O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: Cc1ccc(C=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc2ccc(C)c(C)c2)cc1C
Temperature: 21 °C
Reaction time: 6 h
Yield: 0.5 %

Procedure:
A 500 ml four-necked flask was charged with a 70 wt % aqueous solution of 143 g (0.55 mole) of D-sorbitol, 73.7 g (0.55 mole) of 3,4-dimethylbenzaldehyde and 12 g of 50 wt % sulfuric acid. The air inside the system was replaced with nitrogen gas. The contents of the flask were stirred at a temperature of 21° C. for 6 hours. The obtained reaction mixture was analyzed by GC. It was found that mono(3,4-dimethylbenzylidene)-D-sorbitol was produced in a yield of 70% and 0.5% or less of bis(3,4-dimethylbenzylidene)-D-sorbitol was also produced.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:24])=[C:21]([F:23])[F:22].C1(O)C=CC=CC=1>O.CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1F
Reactant: FC(F)=C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 0.33 h
Yield: 98 %

Procedure:
0.93 Gram of 4-acetylamino-3-fluorophenol, 0.15 g of potassium carbonate and 15 ml of dimethylformamide were added to a reactor and stirred for 20 minutes at an oil bath temperature of from 60° to 70° C. Thereafter, this solution was violently stirred at the same temperature for 1 hour under the stream of a tetrafluoroethylene gas in excess of said phenol. The reaction solution was cooled and after adding water, extracted with two 100-ml portions of diethyl ether. The ether layers were combined, washed with water, dried and concentrated to obtain a crude product. This crude product was subjected to chromatography on silica gel to obtain 1.46 g of 4-acetylamino-3-fluoro-1-(1,1,2,2-tetrafluoroethoxy)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.Cl.[CH:18]1([NH:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:24]=[C:10]([CH3:11])[CH:9]=2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: NNC1CCCC1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(Br)cc2[N+](=O)[O-])n(C2CCCC2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1.0 g of 1-(4-bromo-2-nitrophenyl)butane-1,3-dione in 10 ml of acetic acid was added 501 mg of cyclopentylhydrazine hydrochloride, followed by stirring at 100° C. for 1 hour and 30 minutes. The reaction mixture was concentrated, and to the obtained residue was added ethyl acetate. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 770 mg of 5-(4-bromo-2-nitrophenyl)-1-cyclopentyl-3-methyl-1H-pyrazole.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[Cl:27][C:28]1[CH:53]=[CH:52][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([S:40]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]3[C:49](O)=[O:50])(=[O:42])=[O:41])[CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1.C1C[C@H](C(O)=O)NCC1.[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[C:2]([O:6][NH:7][C:49]([C@H:44]1[CH2:45][CH2:46][CH2:47][CH2:48][N:43]1[S:40]([N:37]1[CH2:36][CH2:35][CH:34]([C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([Cl:27])=[CH:53][CH:52]=2)[CH2:39][CH2:38]1)(=[O:42])=[O:41])=[O:50])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(S(=O)(=O)N2CCCC[C@@H]2C(=O)O)CC1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)[C@H]1CCCCN1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 65 %

Procedure:
O-tert-butylhydroxylamine hydrochloride (127 mg, 1.01 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol), N,N-dimethylaminopyridine (41 mg, 0.34 mmol), and N-methylmorpholine (0.15 ml, 1.3 mmol) were added to a solution of 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (140 mg, 0.34 mmol), [prepared by proceeding as described in Example 9, but replacing D-valine and 4-(4-chlorophenoxy)piperidinesulfamoyl chloride with D-pipecolinic acid and 4-(4-chlorobenzoylpiperidinesulfamoyl chloride, respectively], in methylene chloride (2 ml). After stirring overnight, the reaction mixture was diluted with ethyl acetate, washed with 1M HCl, and brine, and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexane) to give N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (65%).