Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[O:6]/[C:5]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]2)=[O:21])[CH:14]=1.CN(C)C=O.O.[NH2:36][NH2:37]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:37][N:36]=[C:5]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]2)=[O:21])[CH:14]=1
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4ccc(Cl)cc43)ccc2F)CC1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccc(Cl)cc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
(Z)-5-chloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1 (3H)-one (66) (53 mg, 0.13 mmol) was suspended in water (1.5 mL) and N,N-dimethylformamide (0.5 mL) and treated with Hydrazine monohydrate (35 μl, 0.72 mmol). The resulting mixture was stirred at 105° C. for 1 hour. The reaction mixture was cooled and diluted with water (˜5 mL) and mixture extracted with DCM (2×5 mL). Combined organics were evaporated to dryness to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (13 mg, 24% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.38 (1H, m), 1.40-1.50 (1H, m), 1.49-1.76 (1H, m), 1.83-1.91 (1H, m), 3.01-3.09 (1H, m), 3.25 (3H, s), 3.26-3.37 (2H, m), 3.40-3.46 (1H, m), 3.88-3.96 (1H, m), 4.34 (2H, s), 7.22 (1H, t), 7.35-7.42 (2H, m), 7.87 (1H, dd), 8.02 (1H, d), 8.26 (1H, d), 12.68 (1H, s); m/z (LC-MS, ESI+), RT=2.24 (M+H 430.6).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1>C(O)C>[CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:24]3\[C:25](=[O:30])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[CH:29][CH:28]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCNCCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCNCCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 90 °C
Yield: 80.9 %

Procedure:
5-(2-Ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 62j (45 mg, 0.118 mmol) was dissolved in 5 ml of ethanol under stirring, and added with 5-fluoro-1,3-dihydro-indol-2-one (16 mg, 0.106 mmol) and piperidine (0.15 ml, 1.49 mmol) to the solution. Upon completion of the addition, the reaction mixture was refluxed at 90° C. in an oil bath for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, added with a little ethanol, and filtered to obtain the title compound (Z)-5-(2-ethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 62 (34 mg, yield 76%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:41]3[C:42]([CH3:56])=[C:43]([NH:48][C:49](=[O:55])[CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:44]([CH3:47])=[C:45]([CH3:46])[C:40]=3[O:39][CH2:38]2)=[CH:33][C:32]=1[O:57][CH3:58])(=O)[CH3:29].O>C1(C)C=CC=CC=1>[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:41]3[C:42]([CH3:56])=[C:43]([NH:48][C:49](=[O:55])[CH2:50][C:51]([CH3:53])([CH3:54])[CH3:52])[C:44]([CH3:47])=[C:45]([CH3:46])[C:40]=3[O:39][CH2:38]2)=[CH:33][C:32]=1[O:57][CH3:58])([CH3:29])=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of potassium tert-butoxide (818 mg, 7.29 mmol) in toluene (45 mL) was added methyl triphenylphosphonium iodide (2.94 g, 7.29 mmol) and the resulting mixture was stirred at 120° C. for 1 hour under an argon atmosphere. To the reaction solution was added N-(3-(4-acetyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (2.32 g, 5.48 mmol) obtained in Example 183 and the resulting mixture was stirred at 120° C. for 2 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.93 g (yield: 84%) of the title compound. Melting point: 186-187° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1Cl)[CH3:2].[NH:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1[N:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1)[CH3:2]
Reactant: O[C@@H]1CCNC1
Reactant: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinic acid ethyl ester (Stage 72.5, 3.00 g, 7.7 mmol), (R)-3-pyrrolidinol (0.807 g, 9.26 mmol) and DIPEA (2.19 g, 17.0 mmol) in iPrOH (50 mL) was stirred at 22° C. for 60 min. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc, washed with sat. aq. NaHCO3 and brine, dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure to give the title compound as a foam. HPLC (Condition 4) tR=5.63 min, UPLC-MS (Condition 8) tR=1.06 min, m/z=440.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.04 Hz, 3H), 1.79-2.01 (m, 2H), 3.09 (d, J=11.73 Hz, 1H), 3.41 (d, J=8.21 Hz, 1H), 3.54 (dd, J=11.73, 4.30 Hz, 1H), 3.65 (dd, J=10.17, 3.52 Hz, 1H), 4.25-4.39 (m, 3H), 4.96 (d, J=3.13 Hz, 1H), 7.34 (d, J=8.21 Hz, 2H), 7.78-7.90 (m, 2H), 8.36 (d, J=2.35 Hz, 1H), 8.81 (d, J=2.35 Hz, 1H), 10.28 (s, 1H).
Reaction SMILES: [H-].[Na+].C1(S([CH2:12][C:13]2[N:17]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[NH:15][N:14]=2)(=O)=O)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]#[N:33])=[CH:26][CH:25]=1.CO>O1CCCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:31]=[C:32]([NH2:33])[N:14]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:13]3[CH:12]=2)=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(-c2ccc(Cl)cc2)cc2nc(-c3ccco3)nn12
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
0.7 g (0.015 mol) sodiumhydride (55%) were added to a solution of 1.50 g (0.005 mol) 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole in 50 ml tetrahydrofuran. The mixture was refluxed and 0.85 g (0.005 mol) 3-(4-chlorophenyl)-2-propenenitrile in 30 ml tetrahydrofuran were added during, aperiod of 5.5 hours. Boiling was continued for 30 minutes and then 20 ml methanol were added at room temperature. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 99/1 gave 0.57 g (35%) 7-(4-chloro-phenyl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as pale crystals. MS m/e (%): 311 (M+H+, 100).
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12]=3[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36](Cl)=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2([C:36](=[O:37])[CH2:35][C:30]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:28]([Cl:27])[CH:29]=3)[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12]=3[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c3c([nH]c2c1)CCNC3CN1CCCCC1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCCC2)NCCc2[nH]c3ccccc3c21

Procedure:
Prepared as Ex. No. 12, from 1.1 g (4.08 mmoles) of crude 1-(piperidin-1-yl)methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole, 1.12 g (8.10 mmoles) of anhydrous potassium carbonate and 1.1 g (4.92 mmoles) of 3,4-dichlorophenylacetylchloride in 40 ml of dry chloroform.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[O:5][N:4]=4)[CH2:22][CH2:21]3)[CH:7]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cc(CCl)no2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)on4)CC3)no2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)isoxazole (170 mg) and homopiperazine (30 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[Na+]>CS(C)=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:2]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCCCC(Cl)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCC(=Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Yield: 67.4 %

Procedure:
To a solution of 10 g of 1-[2-chloro-2-(2,4-dichlorophenyl)hexyl] imidazole in 100 ml of dimethyl sulfoxide is added 25 ml of 50% sodium hydroxide solution dropwise at room temperature. The reaction mixture is heated at 60° for 2 hours. It is then poured into 300 ml of ice water and extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution and dried over magnesium sulfate. Drying agent is filered and to the filtrate is added concentrated nitric acid dropwise until it is strongly acidic. An oily material settled and is triturated with a 50--50 ether-hexane mixture three times and then back neutralized to its free base with 10% ammonium hydroxide solution. The free base is extracted with ether and the combined ether extracts are washed with water and saturated sodium chloride solution and dried over magnesium sulfate. Solvent is evaporated to give 6 g of a brown oily product.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[C:12]([O:14]C)[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].[CH3:19]O>O>[OH:14][C:12]1[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][CH3:19])[CH:13]=1
Reactant: CO
Reactant: COC(=O)c1cc(C(C)C)c(OC)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(O)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.5 ml) was added to a suspension of methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (418 mg, 1.87 mmol) in methanol (4 ml) and water (2 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford 4-hydroxy-5-isopropyl-2-methoxybenzoic acid (332 mg, 85%) as an off-white solid. 1H NMR (DMSO-d6) 11.88 (1H, br s), 10.11 (1H, s), 7.54 (1H, s), 6.51 (1H, s), 3.75 (3H, s), 3.11 (1H, m), 1.13 (6H, d). MS: [M+Na]+ 233.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]CC)=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(ccn4C)c3)c(Cl)c2Cl)C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1ccc2cc(Sc3ccc(/C=C/C(=O)N4CCCC(C(=O)O)C4)c(Cl)c3Cl)ccc21

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with ethyl ester from Example 337, and KOH with NaOH, to give a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 1.29-1.45 (m, 1H), 1.45-1.78 (m, 2H), 1.78-2.02 (m, 1H), 2.20-2.40 (m, 1H), 2.82 (brt, J=10.5 Hz, 1H), 3.08 (brt, J=10.5 Hz, 1H), 3.80-4.07 (m, 2H), 3.86 (s, 3H), 4.38-4.50 (m, 1H), 6.42 (d, J=8.4 Hz, 1H), 6.54 (d, J=3.0 Hz, 1H), 7.19 (d, J=15.3 Hz, 1H), 7.32 (dd, J=1.8, 8.7 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.67-7.77 (m, 2H), 7.87 (d, J=1.8 Hz, 1H). MS (ESI+) (M+H)+ at m/z 489, 491, 493. Anal. Calcd for C24H22Cl2N2O3S.0.56 CH2Cl2: C, 54.94; H, 4.34; N, 5.22. Found: C, 54.89; H, 4.44; N, 5.32.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:36]([CH3:35])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: CNc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(N(C)c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and N-methylaniline.
Reaction SMILES: [CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][C:5](=O)[C:6]([NH2:8])=[O:7])[CH3:2].Cl.[NH2:16][OH:17]>>[CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][C:5](=[N:16][OH:17])[C:6]([NH2:8])=[O:7])[CH3:2]
Reactant: CCC(CC(=O)C(N)=O)C(C)[N+](=O)[O-]
Reactant: NO
Agent: Cl
Product: CCC(CC(=NO)C(N)=O)C(C)[N+](=O)[O-]
Yield: 69.8 %

Procedure:
4-Ethyl-2-hydroxyimino-5-nitro-hexanamide (15 mg) was prepared in the substantially same manner as that of Example 24 from 4-ethyl-5-nitro-2-oxo-hexanamide (20 mg) and hydroxylamine hydrochloride (14 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[H-].[Na+]>O>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: c1c[nH]cn1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Nc1cc([N+](=O)[O-])c(-n2ccnc2)cc1F

Procedure:
12 g (0.068 mol) of 5-amino-2,4-difluoronitrobenzene were slowly added at 0° C. to a solution of 4.7 g of imidazole (0.069 mol) and 2.1 g of sodium hydride (80% in oil; 0.07 mol) and then stirred at this temperature for several hours. The mixture was then diluted with water and extracted several times with methylene chloride. The residue after drying and evaporation was recrystallized from isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][C:8](=[O:21])[C:9]3[CH:15]=[C:14]([CH:16]([CH3:20])[C:17](N)=[O:18])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.C([OH:26])C.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][C:8](=[O:21])[C:9]3[CH:15]=[C:14]([CH:16]([CH3:20])[C:17]([OH:26])=[O:18])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1
Reactant: CCO
Reactant: COc1ccc2c(c1)Sc1ccc(C(C)C(N)=O)cc1C(=O)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)Sc1ccc(C(C)C(=O)O)cc1C(=O)C2
Reaction time: 7.5 h
Yield: 33 %

Procedure:
To a mixture of 393 mg of 2-(10,11-dihydro-7-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 12 ml of ethanol was added 1.2 g of potassium hydroxide in 3 ml of water, and the mixture was refluxed with stirring for 7.5 hours. The solvent or ethanol was removed by distillation to obtain a mixture, to which was added water, and the resulting mixture was washed with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an orange oil, which was chromatographed over 10 g of silica gel and eluted with chloroform, thereby obtaining 138 mg (yield: 33%) of 2-(10,11-dihydro-7-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow oil.
Reaction SMILES: C(C1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[C:5]([F:16])[CH:4]=1)#N.C1COCC1.CO.[OH-].[Na+].CC[O:28][C:29]([CH3:31])=[O:30]>>[CH2:12]([N:9]([CH2:10][CH3:11])[C:7]([C:6]1[CH:14]=[CH:15][C:31]([C:29]([OH:28])=[O:30])=[CH:4][C:5]=1[F:16])=[O:8])[CH3:13]
Reactant: CCN(CC)C(=O)c1ccc(C#N)cc1F
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(=O)O)cc1F
Temperature: 65 °C
Yield: 66 %

Procedure:
To 4-cyano-2-fluoro-benzoic acid (2.0 g, 12.1 mmol) in DMF (18 mL) at room temperature was added N-ethylethanamine (1.5 g, 2.1 mL, 13.3 mmol) followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.6 g, 12.1 mmol) and diisopropylethylamine (3.9 g, 5.3 mL, 30.3 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc and washed with brine solution. The organics were separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc-DCM (10-100%) as eluent to give 4-cyano-N,N-diethyl-2-fluoro-benzamide (2.0 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=7.8, 1.3 Hz, 1H), 7.47-7.37 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.16 (q, J=7.1 Hz, 2H), 1.24 (td, J=7.1, 2.0 Hz, 4H). To 4-cyano-N,N-diethyl-2-fluoro-benzamide (1.75 g, 7.9 mmol) was added a 2:1 mixture of THF:MeOH (15 mL), followed by 4 N NaOH solution (10 mL, 39.6 mmol) and the reaction mixture was heated at 65° C. for 2.5 hours. The reaction mixture was cooled, diluted with EtOAc and washed with 2 M HCl solution. The organics were separated, dried and concentrated in vacuo to give 4-(diethylcarbamoyl)-3-fluoro-benzoic acid (1.91 g, 66%) as a solid. ESI-MS m/z calc. 239.24. Found 240.2 (M+1); Retention time: 0.99 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: c1nc[nH]n1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cncn1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 56.5 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (1.17 g) and 1H-1,2,4-triazole (404 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (830 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]([OH:7])[CH3:6].[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]([O:7][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:6]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 72 h
Yield: 95.2 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-hydroxy-butyric acid methyl ester (1.85 g, 7.93 mmol) was dissolved in N,N-dimethylformamide (10 mL), under an atmosphere of nitrogen. tert-Butyl(chloro)diphenylsilane (2.89 mL, 11.1 mmol) was added followed by imidazole (1.08 g, 15.9 mmol) and the reaction was left to stir for 72 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a stepwise gradient iso-hexanes/ethyl acetate from 1:0 to 4:1 to afford the title compound (3.56 g, 95%) as a pale Greene oil. 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J=6.6 Hz, 3H), 1.04 (s, 9H), 1.10 (s, 9H), 3.64 (s, 3H), 4.18-4.26 (m, 1H), 4.39-4.50 (m, 1H), 5.34 (d, J=9.9 Hz, 1H), 7.36-7.50 (m, 6H), 7.60-7.69 (m, 2H), 7.71-7.77 (m, 2H). LCMS (m/z) 472.2 [M+H], Tr=4.13 min.