Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)=[O:26]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)CBr)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution containing the product from Example 1B (1.5 g, 6.1 mmol) and AlCl3 (2.4 g, 18 mmol) in 10 mL of dichloromethane at 0° C. was added bromoacetyl bromide (0.55 mL, 6.2 mmol). The mixture was stirred at room temperature for 30 min, to one hour. Upon completion of the reaction as monitored by thin layer chromatography, the reaction mixture was poured into ice-cold water (100 mL), and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure, and the resulting oil was purified by flash chromatography (ethyl acetate/hexane, 1/8) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (m, 2H), 1.19 (t, J=7.06 Hz, 3H), 1.50 (m, 2H), 1.70-1.85 (m, 5H), 2.22 (d, J=6.75 Hz, 2H), 2.56 (m, 1H), 4.07 (q, J=7.06 Hz, 3H), 4.88 (s, 2H), 7.41 (d J=8.28 Hz, 2H), 8.92 (d, J=8.28 Hz, 2H); MS (ESI) m/z 367.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH:26]3[CH2:27][CH2:28][N:23]([CH:20]4[CH2:22][CH2:21]4)[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C1CCN(C2CC2)CC1
Product: Clc1nc(N2CCOCC2)c2sc(CNCC3CCN(C4CC4)CC3)cc2n1
Yield: 57 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-cyclopropyltetrahydro-4(1H)-pyridinone using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-cyclopropylpiperidin-4-yl)methyl-amine as a solid (57% 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 purified by mass directed chromatography (18% yield) to give 339. NMR (CDCl3, 400 MHz), 0.39-0.47 (4H, m), 1.58-1.66 (3H, m), 1.83 (2H, d, J=12.1), 2.19 (2H, t, J=9.9), 2.36 (3H, s), 2.54-2.58 (1H, m), 3.13 (2H, d, J=11.5), 3.88-3.92 (6H, m), 4.03-4.06 (4H, m), 5.22 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=481
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10](Br)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:8][C:7]=2[CH:20]=1.[Li]CCCC.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:26]([OH:28])=[O:27])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:8][C:7]=2[CH:20]=1
Reactant: O=C=O
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)O)cc1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-bromobenzo[b]thiophene (15.0 g, 42.9 mmol) was dissolved in 300 mL of anhydrous THF under N2 and cooled to −70° C. To this solution was added nBuLi (29.6 mL, 47.4 mmol, 1.6 M solution in hexanes) dropwise via syringe. After stirring at −70° C. for 20 min, a steady stream of CO2 (g) was introduced into the reaction mixture for 15 min. The mixture was allowed to gradually warm to 0° C. and then quenched by pouring the mixture into cold 1 N HCl (500 mL). The aqueous layer was extracted with EtOAc (3×300 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to a solid. The crude product was chromatographed (SiO2, 25% EtOAc/hexanes) to provide 9.35 g (69%) of 6-methoxy-2-(4-methoxyphenyl)-3-carboxybenzo[b]thiophene as a white solid. mp 166-170° C. 1H NMR (DMSO-d6) δ (doubling due to rotamers) 13.0-12.8 (bs), 8.10 and 7.68 (d, J=8.1 Hz, 1H), 7.63 and 7.47 (d, J=8.6 Hz, 2H), 7.59 and 7.54 (d, J=2.0 Hz, 1H), 7.10 and 6.97 (dd, J=8.1, 2.0 Hz, 1H), 7.02 (d, J=8.6 Hz, 2H), 3.83 and 3.79 (s, 3H), 3.82 and 3.80 (s, 3H). FD mass spec: 315. Anal. Calcd. for C17H14O4S: C, 64.95; H, 4.49. Found: C, 65.19; H, 4.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[C:10]([CH2:19]Br)[N:9]=2)=[CH:4][CH:3]=1.[CH3:21][O-:22].[Na+].[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH2:19][O:22][CH3:21])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1CBr
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Ethyl 6-(4-fluorophenyl)-2-(bromomethyl)nicotinate (D85) (38 mg, 0.11 mmol) was treated with sodium methoxide (18 mg, 0.34 mmol) in methanol (1 ml) at room temperature for 1 h. 2M Sodium hydroxide solution was then added and the solution stirred for 1 h. The mixture was diluted with water and extracted with EtOAc which was dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (19 mg). MS(ES): MH+ 262, M-H+ 260.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH:18]([N:21]([CH:36]([CH3:38])[CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:20])[CH3:19]>C(O)C.N1CCCCC1>[CH:36]([N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:37])[CH3:38]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (43 mg, 30%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[NH2:21]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:26]3[CH:27]=[CH:28][C:23]([C:20]([NH2:21])=[O:22])=[CH:24][CH:25]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Product: NC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 24 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg) was reacted with 4-carbamoylphenyl boronic acid as in General Procedure 4B to give the title compound as a white solid (24% yield). M.p.>200° C., LCMS: m/z=359.22 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.22 (2H, s), 5.28 (2H, s), 7.24 (1H, m), 7.33 (5H, m), 7.41 (1H, s), 7.56 (2H, d, J=8.6 Hz), 7.88 (2H, d, J=8.3 Hz), 7.96 (1H, bs), 8.04 (1H, d, J=1.8 Hz).
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[N:15]=[C:16]([C:25](OC)=[O:26])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>O1CCCC1>[CH3:13][C:14]1[N:15]=[C:16]([C:25]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:26])[S:17][C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2ccccc2)sc1-c1ccncc1
Reaction time: 1 h
Yield: 33.3 %

Procedure:
n-Butyllithium (14-17% in hexane, 1.2ml) was added to dropwise a stirred solution of aniline (0.12 ml) in dry tetrahydrofuran (3 ml) at room temperature under nitrogen atmosphere. Then, methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (200 mg) was added to a stirred solution at room temperature under nitrogen atmosphere, and the mixture was stirred in the same condition for 1 hour. The resulting precipitates were collected by filtration, and the precipitates were washed with water, and air-dried. The precipitate was recrystallized from benzenepetroleum ether to give 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide (80 mg, yield 33.3%) as colorless plates.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[C:27]([O:31][C:32](NCC(O)=O)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(OC(C)C)(C)C>>[C:27]([O:31][C:32](=[O:33])[NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide hydrochloride (Example 73) and N-(tert-butoxycarbonyl)-glycine (Aldrich) according to the method described in Example 94. Melting Point: 177-179° C. (diisopropylether)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[C:21](=[O:28])([O:25][CH2:26][CH3:27])OCC>O>[O:18]=[C:4]1[CH:3]=[C:2]([CH:1]([C:21]([O:25][CH2:26][CH3:27])=[O:28])[C:21]([O:25][CH2:26][CH3:27])=[O:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(=O)n(-c2ccccc2)c2ccccc12
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cc(=O)n(-c2ccccc2)c2ccccc12

Procedure:
A mixture of 1,2-dihydro-4-methyl-2-oxo-1-phenylquinoline (4.7 g.), sodium hydride (4.8 g., 60% w/w dispersion in oil, washed as in Example 1) and diethyl carbonate (50 ml.) was stirred under reflux for 2 hours. Any excess of sodium hydride was then destroyed by addition of methanol to the cooled suspension, and the mixture was then poured into ether (1 l.). The yellow precipitate was collected by filtration, and washed with ether (200 ml.). It was suspended in ethanol (50 ml.), concentrated hydrochloric acid was added to give a pH of 3, and the resultant solution was poured into water (200 ml.). The precipitate was extracted into ether, and the combined extracts were washed with water, dried over magnesium sulphate, and evaporated in vacuo. A sample of the residual solid was recrystallised from a mixture of benzene and cyclohexane to give diethyl 1,2-dihydro-2-oxo-1-phenylquinol-4-ylmalonate, m.p. 101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Amino-3-nitrobenzoic acid may be prepared as described in Chapman, E. and Stephen, H., "Preparation of phthalmic acids and their conversion to anthranilic acids," J. Chem. Soc., (1925), 1151. To a mixture of this acid (14.00 g, 76.9 mmol) and cesium carbonate (20.00 g, 61.5 mmol) in dimethylformamide (150 mL) at 0° C. methyl iodide (12.00 g, 84.5 mmol) was added with stirring. After 20 minutes, it was warmed to room temperature and stirred for 3 hours. Most of the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (250 mL) and water (100 mL). The organic layer was separated, the aqueous layer was washed with ethyl acetate (250 mL) and the combined organic extract was dried over magnesium sulfate. After concentrating, the residue was triturated with ether to obtain the first crop of product as a yellow solid (3.20 g). The filtrate solution was concentrated, and the residue was passed through a flash column on silica gel eluting with 4:1 hexane:ethyl acetate to afford a slightly impure product. This material was triturated with methanol to obtain a pure second crop of product (9.10 g); total 12.3 g in 82% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[O:45]1[C:49]2[CH:50]=[CH:51][C:52]([S:54]([N:57]([CH2:82][CH:83]([CH3:85])[CH3:84])[CH2:58][C@@H:59]([OH:81])[C@@H:60]([NH:69][C:70](=[O:80])[O:71][C@@H:72]3[C@H:79]4[C@H:75]([O:76][CH2:77][CH2:78]4)[O:74][CH2:73]3)[CH2:61][C:62]3[CH:67]=[CH:66][C:65](O)=[CH:64][CH:63]=3)(=[O:56])=[O:55])=[CH:53][C:48]=2[O:47][CH2:46]1>C(Cl)Cl>[O:45]1[C:49]2[CH:50]=[CH:51][C:52]([S:54]([N:57]([CH2:82][CH:83]([CH3:85])[CH3:84])[CH2:58][C@@H:59]([OH:81])[C@@H:60]([NH:69][C:70](=[O:80])[O:71][C@@H:72]3[C@H:79]4[C@H:75]([O:76][CH2:77][CH2:78]4)[O:74][CH2:73]3)[CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:28][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:66][CH:67]=3)(=[O:55])=[O:56])=[CH:53][C:48]=2[O:47][CH2:46]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: OCCc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCc2ccccc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of 66 mg (0.25 mmol) of triphenylphosphine and 30 μL (0.25 mmol) of phenethyl alcohol in 3 mL of anhydrous CH2Cl2 was added 58 mg (0.25 mmol) of di-tert-butyl azodicarboxylate. The resulting solution was stirred at RT for 5 minutes and was then treated with a solution of 50 mg (0.084 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate in 2 mL of CH2Cl2. After stirring at RT for 1.5 hours the solution was concentrated to dryness and the residue purified by flash chromatography (SiO2, 4:6 hexane/EtOAc) to give the desired product as a white foam in 72% yield. 1H NMR (CDCl3): 7.34-7.17 (m, 6H), 7.15 (s, 1H), 7.07 (d, 2H), 6.86 (d, 1H), 6.78 (d, 2H), 6.03 (s, 2H), 5.61 (d, 1H), 4.98 (m, 1H), 4.86 (d, 1H), 4.09 (t, 2H), 3.92 (m, 1H), 3.84-3.56 (m, 6H), 3.17-3.01 (m, 3H), 3.00-2.81 (m, 4H) 2.80-2.64 (m, 2H), 1.78 (m, 1H), 1.56 (m, 1H), 1.47 (m, 1H), 0.91 (d, 3H), 0.85 (d, 3H). MS(ESI): 697(M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=1.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([NH:1][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[CH:3][C:4]=1[F:13])[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)c(F)c1
Temperature: 130 °C

Procedure:
A mixture of 2.6 g of ethyl 4-amino-2-fluorobenzoate 4.5 g of hexadecylbromide, 2.0 g of anhydrous potassium carbonate and 20 ml of hexamethylphosphoramide is heated to 130° C. for 22 hours. The mixture is cooled, diluted with 200 ml of water, and extracted twice with ethyl ether. The combined extracts are washed with water, dried, and the ether evaporated and the residue upon recrystallization from hexane yields ethyl-2-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:16])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[H-].[Na+].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1c2ccc(C(=O)NC(=O)c3ccccc3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[Step 2] 33.2 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxamide was dissolved in 1 mL of tetrahydrofuran, and 10.3 mg of sodium hydride was added to the solution at 0° C. The mixture was stirred for 30 minutes at room temperature. Subsequently, 10.3 μL of benzoyl chloride was added dropwise to the mixture, and the mixture was stirred for 12 hours at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform:methanol=10:1), and then was recrystallized from ethyl acetate-hexane. Thus, 23.6 mg (56.8%, cis:trans=20:1) of the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[C:16](=[N:17][C:18]([C:24]5[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=5)=[CH:19]4)[C:15]=3[CH:31]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:33].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[CH:19]=[C:18]([C:24]5[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=5)[N:17]=[C:16]4[C:15]=3[CH:31]=2)=[O:33])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cccnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)C)CC3)ccc1OCC2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)C)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidin-4-ylsulfanyl)-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 7 (70 mg, 0.161 mmol) in DCM (10 mL) was added TFA (62 μL, 0.805 mmol) followed by a solution of m-CPBA (31 mg, 0.177 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 5-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 204 as a pale orange foam (65 mg, 90%). LCMS: RT1.92 min [M+H]+ 451.1. 1H NMR (DMSO, 400 MHz): δ 8.66 (1H, d, J=2.27 Hz), 8.40 (1H, dd, J=4.69, 1.63 Hz), 7.89 (1H, s), 7.64 (1H, ddd, J=7.65, 1.72, 0.84 Hz), 7.49 (1H, dd, J=8.50, 2.30 Hz), 7.23 (1H, d, J=8.72 Hz), 7.18 (1H, dd, J=7.96, 4.16 Hz), 4.60-4.53 (4H, m), 2.85-2.77 (2H, m), 2.73-2.59 (5H, m), 2.13-2.02 (2H, m), 1.76 (1H, bd, J=12.29 Hz), 1.58 (1H, bd, J=12.37 Hz), 1.52-1.38 (2H, m), 0.90 (6H, d, J=6.54 Hz)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:18]C)=[O:17])=[C:12]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[Si:1]([O:8][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([OH:18])=[O:17])=[C:12]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
To a solution of 1.875 g (4.38 mmol) of the product of Step K in methanol (20 mL) was added 1N NaOH (4.82 mL, 4.82 mmol) at rt. The solution was stirred at rt for 3 hours. After the solvent was evaporated under reduced pressure, the residue was dissolved in H2O (30 mL) and washed with ethyl acetate (30 mL). The aqueous layer was acidified to pH=3 with 2N HCl. A milky emulsion was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, and was dried over anhydrous MgSO4. Concentration afforded 0.929 g of the title compound as a colorless glass.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.Cl.[N:15]([O-])=[O:16].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CCCCn1c(N)cc(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 50.6 g (0.276 mol) of 6-amino-1-butyl-2,4-(1H,3H)-pyrimidinedione (VIII) dissolved in 1.8 l of water at 80° C. was added 60 ml of 5 N HCl and 20 g (0.29 mol) of NaNO2 which were dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 52.8 g (97%) (IX), NMR.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:51]=[CH:50][C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][CH2:28][N:29]([CH2:39][C:40]3[CH:49]=[CH:48][C:43]([C:44]([O:46]C)=[O:45])=[CH:42][CH:41]=3)[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:34]([CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=1)[CH2:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:18]1[CH:50]=[CH:51][C:15]([CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)([OH:36])=[O:35]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)Cc1ccc(C(=O)OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccc(O)cc2)cc1)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 mg (0.037 mmol) of methyl 4-{[{2-[2-({4-[2-(4-{[tert-butyl(dimethyl)-silyl]oxy}phenyl)ethyl]benzyl}oxy)phenyl]ethyl}(5-ethoxy-5-oxopentyl)amino]-methyl}benzoate from XXI are dissolved in 10 ml of THF. 0.03 ml of tetrabutylammonium fluoride (1M solution in THF) are added, and the solution is stirred at RT for 1 hour. The solvents are evaporated under reduced pressure. The residue is dissolved in 2 ml of methanol. 0.05 ml of aqueous sodium hydroxide solution, 45%, and 0.2 ml of dichloromethane are added, and the solution is stirred at RT for 8 hours. The mixture is concentrated, water is added and the solution is acidified using sulphuric acid. The solid is filtered off and dried.