Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[CH2:7]1[O:9][CH2:8]1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([OH:29])(=[O:28])[C:25]([CH3:27])=[CH2:26].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[CH:16]([CH2:12][C:11](=[CH2:13])[C:10]([OH:15])=[O:14])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[CH2:8]1[O:9][CH2:7]1.[C:24]([OH:29])(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CO1
Product: C=C(CC=Cc1ccccc1)C(=O)O
Reaction time: 0.25 h

Procedure:
A reactor to which a stirring rod and a thermometer was set was charged with 683 parts of water, 11 parts of a sodium salt of sulfate of methacrylic acid ethylene oxide adduct (ELEMINOL RS-30, manufactured by Sanyo Chemical Industries, Ltd.), 138 parts of styrene, 138 parts of methacrylic acid, and 1 part of ammonium persulfate, which was stirred at 400 rpm for 15 minutes, and a white emulsion was obtained. This was heated until a temperature in the system reached 75° C. and reacted for 5 hours. Further, it was added with 30 parts of a 1-% ammonium persulfate aqueous solution and aged at 75° C. for 5 hours, and an aqueous dispersion of a vinyl resin (a copolymer of styrene—methacrylic acid—sodium salt of sulfate of methacrylic acid ethylene oxide adduct) [fine particles dispersion 1] was obtained. A volume-average particle diameter of the obtained [fine particles dispersion 1] was measured with LA-920 (manufactured by Horiba Ltd.) and found to be 0.14 μm. A part of [fine particles dispersion 1] was dried and the resin content was isolated.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:34]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([Cl:34])=[N:24][NH:25]2)=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1ccc2cn[nH]c2c1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1ccc2c(Cl)n[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
Under nitrogen atmosphere, 6-tert-butyldiphenylsilyloxyindazole (29.246 g) which can be prepared according to the method described in Reference example 36, etc. was dissolved in dehydrated THF (200 mL). After cooling to 0° C., potassium tert-butoxide (18.2190 g; manufactured by Kanto Chemical Co., Inc.) and N-chlorosuccinimide (17.0497 g; manufactured by Kanto Chemical Co., Inc.) were added and then stirred for four hours while increasing the temperature from 0° C. to room temperature. The reaction solution was added to a saturated aqueous solution of ammonium chloride and extraction was carried out twice with ethyl acetate. The organic layer was washed once with brine and dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=88:12→67:33) to obtain the title compound (18.592 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([C:47]2[CH:56]=[CH:55][CH:54]=[C:49]([C:50]([NH:52][NH2:53])=[O:51])[C:48]=2[OH:57])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:53][NH:52][C:50]([C:49]1[C:48]([OH:57])=[C:47]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:56]=[CH:55][CH:54]=1)=[O:51])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NNC(=O)c1cccc(-c2ccccc2)c1O
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NNC(=O)c1cccc(-c2ccccc2)c1O
Yield: 23.8 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (93 mg, 0.17 mmol) and 3-phenylsalicylic acid hydrazide (45 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (30 mg). 1H-NMR (400 MHz, CD3OD) d 4.80 (s, 2H), 4.27 (dd, J=4.9 Hz, J=9.8 Hz, 1H), 3.04 (m, 1H), 2.94 (m, 1H), 2.72 (dd, J=9.3 Hz, J=13.7 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3280, 1694, 1653 cm−1; HRMS m/z 740.2666 (calc. of monoisotopic mass for C39H40N4O11 gives 740.2694).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][OH:32])[N:9]=1.C(NC(C)C)(C)C.CN(C1C=CC=CN=1)C.[C:49]1(=[O:55])[O:54][C:52](=[O:53])[CH2:51][CH2:50]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][O:32][C:49](=[O:55])[CH2:50][CH2:51][C:52]([OH:54])=[O:53])[N:9]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2CO
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2COC(=O)CCC(=O)O
Temperature: 25 °C
Yield: 25.7 %

Procedure:
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (2.0 g, 4.3 mmol) was dissolved in 80 mL THF, and diisopropylamine (0.78 g, 5.6 mmol), dimethyamino pyridine (52 mg, 0.4 mmol) and succinic anhydride (703 mg, 7.0 mmol) were added while stirring at room temperature. The reaction mixture was stirred for 16 hours at room temperature, then partitioned between water and ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and purified by flash chromatography (silica gel, hexanes/EtOAc 1:1 to EtOAc/AcOH 100:1) to give 0.62 g of succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-hydroxy-propylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl]ester, MS (M+H)=562
Reaction SMILES: COCCOC[O:7][C@@H:8]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:10]([C@@H:11]([O:35]COCCOC)[CH2:12][C@@H:13]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:9]1.CCOCC>C(Cl)Cl.CO.[Br-].[Zn+2].[Br-]>[OH:7][C@@H:8]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:10]([C@@H:11]([OH:35])[CH2:12][C@@H:13]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])[CH2:9]1
Reactant: COCCOCO[C@@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCC=C(C)C)CC[C@H]4[C@@H]3C[C@H](OCOCCOC)[C@@H]2C1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
2.0 g of 3α,6α-bis(β-methoxyethoxymethoxy)-5β-cholest-24-ene, prepared according to Example V, was dissolved in a mixture of 20 ml of methylene chloride and 0.30 ml of methanol, and the solution was stirred with 5 g of zinc bromide for 18 hours. Then, ether was added, the mixture washed with water, the organic layer dried, the solvent evaporated, the residue washed with petroleum ether and dried. From nmr and ir data, the residue was identified as 3α,6α-dihydroxy-5β-cholest-24-ene, the same product as obtained by the acid hydrolysis of the 2-THP, t-Bu, Me3Si and Me2 t-BuSi ethers in Examples VI-IX.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: O=C1CN(CCc2ccc(Cl)cc2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(Cl)cc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 70.5 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (250 mg, 0.66 mmol) and 4-(4-chlorophenethyl)piperazin-2-one (157 mg, 0.66 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (250 mg, 70%) as a colorless oil: ESI MS m/z 537 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
To a mixture of 5.0 g (31.80 mmole) of 3-fluoro-4-nitrophenol, 8.32 g (41.31 mmole) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester and 14.32 g (54.06 mmole) of triphenylphosphine in 100 mL of tetrahydrofuran was added 8.4 mL (54.06 mmole) of diethyl azodicarboxylate. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 6.94 g of 4-(3-fluoro-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (IV.21a).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:21]([O-])=O)[CH:8]=2)[O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(Oc2ccnc(O)c2)C1O
Agent: [Pd]
Solvent: CO
Product: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy )-6-nitro-3-chromanol in 25 ml of methanol is hydrogenated at 20° and 1 bar on 0.5 g of 5% Pd-C to completion. The mixture is filtered, evaporated and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC1C=CC=CC=1.[Br:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:23][CH2:22][CH2:21][Br:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: BrCCCBr
Reactant: Cc1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Nc1ccccc1
Solvent: CC(C)=O
Product: Cc1cc(OCCCBr)c2ccccc2n1
Yield: 64 %

Procedure:
A mixture of 2-methylquinolin-4-ol (1.59 g, 10 mmol) (synthesized from aniline and acetoacetic ester according to a procedure known in the art: see Leonard et al. (1946) J. Am. Chem. Soc. 68:1279-1281), 1,3-dibromopropane (8.08 g, 40 mmol) and potassium carbonate (1.659 g, 12 mmol) in acetone (50 mL) was refluxed until the starting material disappeared. The reaction mixture was filtered and after evaporation of solvent residue was purified by column chromatography on silica gel (1% MeOH: 99% CH2Cl2 as eluent). The product was obtained as light yellow solid (1.793 g, 64%). 1H NMR (400 MHz, CDCl3): 2.48 (2H, m), 2.69 (3H, s), 3.69 (2H, t, J=6.3 Hz), 4.33 (2H, t, J=5.8 Hz), 6.6 (1H, s), 7.43 (1H, t, J=7.5 Hz), 7.66 (1H, t, J=7.8 Hz), 7.95 (1H, d, J=8.5 Hz), 8.12 (1H, d, J=8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[C:5]2[N:6]([C:8]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.C(O)C.NN>CC(=O)OCC>[NH2:23][CH2:22][C:4]1[C:5]2[N:6]([C:8]([C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[O:21])=[C:9]([CH3:11])[N:10]=2)[N:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1nc2c(CN3C(=O)c4ccccc4C3=O)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc2c(CN)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine 2-((6-chloro-3-(4-chloro-2-fluorobenzoyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)isoindoline-1,3-dione (7.30 g, 15.1 mmol), ethanol (200 mL), and hydrazine (1.45 mL, 3 equiv.) in a round bottom flask and place under nitrogen. Stir for 2 days at RT. Heat for 2 h at 50° C. then concentrate the reaction in vacuo. Dilute with EA. Wash the organics with 1 N HCl (aq) to pull product into the aqueous layer. Make the aqueous layer basic with 1 N NaOH (aq) and extract with EA. Wash the EA layer with aqueous saturated sodium chloride, and dry over anhydrous magnesium sulfate. Filter and concentrate in vacuo to give the title compound crude (1.2 g, 23%) as a light green solid. MS=355.0, 353.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[CH3:27])#[N:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[C:5]([Cl:22])=[CH:4][C:3]([F:23])=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]([C:24]#[N:25])([CH3:27])[CH3:28])[CH:30]=4)[CH:7]=3)[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)c(F)cc3Cl)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)c(F)cc3Cl)nc2s1
Yield: 66.8 %

Procedure:
A solution of N-{5-[(5-amino-2-chloro-4-fluorophenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (100 mg, 283 μmol), 3-(1-cyano-1-methylethyl)benzoic acid (128 mg, 680 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (258 mg, 680 μmol) in pyridine (3 mL) was stirred at 90° C. for 9 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/90→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (99 mg, 67%) as colorless crystals.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:23][C:18]2[CH:19]=[N:20][N:21]([CH3:22])[C:17]=2[C@H:5]2[O:4][CH2:3][C@@H:2]([F:1])[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6]2)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1

Procedure:
Following the procedure for Example 65, starting from tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (intermediate 80) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with 6-bromo-5-fluoro-pyridine-2-carboxylic acid (see US2010/56576 A1) gave tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate.
Reaction SMILES: C(C1C=CC(C(O)=O)=CC=1)(=O)CCCCCCCC.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:42])[CH:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:41][CH:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)=[CH:28][CH:29]=1)=[O:42]
Reactant: CCCCCCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 32.9 %

Procedure:
To 10 ml of methylene chloride were added 85 mg (0.32 mmol) of 4-nonanoyl benzoic acid obtained in Example 33, 100 mg (0.32 mmol) of (+)-4-hydroxy-4'-(2-methyloctanoyl) biphenyl and 6 mg of 4-dimethylamino pyridine, which was added with 73 mg (0.35 mmol) of N,N'-dicyclohexylcarbodiimide. This mixture was reacted by heating under reflux for 4 hours, and the precipitated solid was filtered off. The filtrate was condensed, isolated by a column chromatography of silica gel and recrystallized with ethyl alcohol to obtain 31 mg (yield 18%) of white 4-(2-methyloctanoyl) biphenyl, 4-nonanoyl benzoic acid ester having the aforementioned physical and chemical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=O)[C:12]3[CH:11]=[N:10][N:9]([CH3:16])[C:8]=3[NH:7][C:6]=2[CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][CH2:13][C:12]3[CH:11]=[N:10][N:9]([CH3:16])[C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2=O
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a suspension of 6-chloro-3-methyl-4,9-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-10-one from Example E1.3 (5.56 g, 22.4 mmol) in anhydrous THF (200 ml) at 0° C. was added lithium aluminium hydride (4.24 g, 112 mmol), and the resulting suspension was heated at reflux for 18 h, then allowed to cool to room temperature. A further portion of lithium aluminium hydride (4.24 g, 112 mmol) was added, and the mixture was heated at re-flux for 18 h. The mixture was cooled to 0° C., 35% ammonia solution (10 ml) was added dropwise over 15 min and the mixture was stirred at room temperature for 30 min. The resulting suspension was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 0.5% 35% ammonia:5% methanol:dichloromethane) to yield the title compound (3.88 g, 74%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:19]2[B:20]([OH:23])[O:21][CH2:22][C:18]=2[CH:17]=[CH:16][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:25]I.[NH4+].[Cl-]>CN(C=O)C>[C:3]([O:7][C:8](=[O:24])[N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:19]2[B:20]([OH:23])[O:21][CH2:22][C:18]=2[CH:17]=[CH:16][CH:15]=1)[CH3:25])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCCOc1cccc2c1B(O)OC2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(CCCOc1cccc2c1B(O)OC2)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaH (60% dispersion in mineral oil, 0.082 g, 2.05 mmol) was added portionwise to a solution of [3-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-propyl]-carbamic acid tert-butyl ester (0.212 g, 0.690 mmol) and MeI (1.03 mL, 2.07 mmol) in anhydrous DMF (5 mL) at 0° C. The reaction was then stirred at rt for 2 h. The mixture was cooled to 0° C., acidified to pH 6 using a sat. NH4Cl, and then extracted with EtOAc. The organic fractions were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (40% EtOAc/hexane) to give the title compound as a colorless oil: yield 0.17 g (77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(Cl)ccc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
A solution of 6-methoxyquinoline N-oxide (5.0 g, 29 mmol) in CHCl3 (30 mL) was treated by slow addition of POCl3 (5.3 mL, 57 mmol) at 0° C. The mixture was heated at 80° C. for 14 hours. The mixture was cooled and poured onto ice. After stirring for 30 min., the aqueous layer was adjusted to pH 9 by Na2CO3 addition. The mixture was extracted with CH2Cl2. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave 2.5 g (46%) of 2-chloro-6-methoxyquinoline as a white solid, (M+) 193(100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH:28]=[C:27]([C:30](O)=[O:31])[O:26][C:25]=2[CH:33]=1>>[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH:28]=[C:27]([C:30]([N:9]3[CH2:10][CH2:11][N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:3]=4[O:2][CH3:1])[CH2:7][CH2:8]3)=[O:31])[O:26][C:25]=2[CH:33]=1
Reactant: O=C(O)C1=COc2ccc(O)cc2O1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Product: COc1ccc(CN2CCN(C(=O)C3=COc4ccc(O)cc4O3)CC2)c(OC)c1OC
Yield: 73 %

Procedure:
That compound is obtained in a yield of 73% starting from 1-(2,3,4-trimethoxybenzyl)piperazine and 7-hydroxy-1,4-benzodioxin-2-carboxylic acid.