Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[CH:16][N:17]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:17][CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[N:14]=1
Reactant: FC(F)(F)c1cc(Cl)c(-c2ncc[nH]2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 70 °C

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (5.62 g, 0.02 mol), nitric acid (70% w/w, 5.6 ml) and sulphuric acid (98% w/w, 5.6 ml) was strirred and heated at 70° C. for a total of 51 hours. After cooling the ceaction mixture was poured into a mixture of ice and water (approximately 75 ml) and the precipitated solid was filtered off. It was purified by mplc on silica eluted with a mixture of ethyl acetate and dichloromethane (1:20) to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitroimidazole (4.21g), m.p. 254°-255° C., as a cream crystalline solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[NH2:25][C:23](=[O:24])[C@@H:22]([NH:21][C:18](=[O:20])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:8]=1)[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCc2ccccn2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189 b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=383.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[Cl-:16].CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: [Cl-]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalkyl chloride and DMF in chloroform at room temperature followed by evaporation in vacua.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[C:14]1([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:20]([N:11]1[N:12]=[N:13][C:9]([C:4]2[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:10]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: Brc1cc(Br)cc(-c2nnn[nH]2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(Br)cc(-c2nnn(C(c3ccccc3)c3ccccc3)n2)c1
Temperature: 100 °C
Yield: 85.1 %

Procedure:
A suspension of 5-(3,5-dibromophenyl)-1H-tetrazole (6.08 g, 20.00 mmol), diphenylmethanol (3.68 g, 20.00 mmol) and TsOH.H2O (0.38 g, 2.00 mmol) in toluene (50.0 mL) was heated to 100° C. until a clear solution was obtained. The solution was cooled to rt, and filtered. The filtration was concentrated, and the residue was purified by recrystallization in ether and hexane to afford 8.00 g (85%) of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:31])[C:7](=[O:30])[C:8]3[CH:18]=[C:17]([CH2:19]NC4C=CC=C([N+]([O-])=O)C=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH-].[Na+].[C:34]([OH:37])(=O)[CH3:35]>Cl>[NH2:6][C:5]1[CH:11]=[C:34]([O:37][CH2:19][C:17]2[CH:16]=[N:15][C:9]3[N:10]([CH2:13][CH3:14])[C:11]4[N:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[N:6]([CH3:31])[C:7](=[O:30])[C:8]=3[CH:18]=2)[CH:35]=[CH:3][CH:4]=1
Reactant: CCN1c2ncc(CNc3cccc([N+](=O)[O-])c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN1c2ncc(COc3cccc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 17 h

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-(3-nitrophenylamino)methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.080 g, 0.18 mmol) was dissolved in acetic acid (5 mL) and treated with a solution of stannous chloride dihydrate (0.154 g, 0.68 mmol) in concentrated hydrochloric acid (2 mL). After stirring for 17 hours the resulting mixture was made alkaline with 50% aqueous sodium hydroxide and extracted with dichloromethane (8×20 mL). The combined organics were dried over sodium sulfate, concentrated and the residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate gradient) to the title compound (0.046 g, 62%), m.p. 148°-149° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[Br:29][CH2:30][CH2:31]Br.O>C(#N)C>[Br:29][CH2:30][CH2:31][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc(N(c2ccc(Cl)cc2)c2ccc(OCCBr)cc2)cc1
Temperature: 25 °C

Procedure:
To a 250 mL rbf was added cesium carbonate (4.93 g, 15.14 mmol) and anhydrous acetonitrile (50 mL). A solution of 4-(bis(4-chlorophenyl)amino)phenol (69, 2.5 g, 7.57 mmol) in acetonitrile (25 mL) was added, and an immediate light purple colour was observed. 1,2-dibromoethane (7.11 g, 37.9 mmol) was added and the reaction was heated to reflux for 5 days. After cooling to RT, the reaction mixture was poured into water (250 mL), mixed well and separated. The aqueous portion was extracted with EtOAc (2×100 mL) and the combined organics were washed with water (2×250 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. Flash chromatography (2% EtOAc/hexanes) afforded 70 as a clear, colourless oil (1.42 g, 43%).
Reaction SMILES: [C:1]([O:16]CC1C=CC=CC=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:46][CH2:47][C@@H:48]([C@H:50]([C@@H:52]([C@@H:54]([CH2:56][OH:57])[OH:55])[OH:53])[OH:51])[OH:49]>CN(C=O)C.O>[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:46][CH2:47][C@@H:48]([C@H:50]([C@@H:52]([C@@H:54]([CH2:56][OH:57])[OH:55])[OH:53])[OH:51])[OH:49])=[O:16])([OH:14])=[O:13]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])CCCCCCCCCCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCCCCCCCCCC(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Monobenzyl dodecanedioate (530 mg, 1.7 mmol) was dissolved in 10 mL of DMF, to which EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) (325 mg, 1.7 mmol) and HOBt (1-hydroxybenzotriazole) (230 mg, 1.7 mmol) were added. The mixture was stirred at room temperature for one hour and then D-glucamine (380 mg, 1.9 mmol) was added. The mixture was stirred at room temperature overnight, poured into 50 mL water, agitated and filtered to give the desired amide, of formula IIa in 95% yield. NMR (DMSO-D-6)7.70(brm, 1H), 7.30(m, 5H), 5.07(s, 2H), 4.73(d, 1H, J=4.5 Hz), 4.44(d, 1H, J=5.4 Hz), 4.36(d, 1H, J=6.0 Hz), 4.32 (t, 1H, J=5.7 Hz), 4.24(d, 1H, J=6.6 Hz), 3.58–3.52(m, 3H), 3.50–3.40(m, 3H), 3.21(m, 1H), 3.00(m, 1H), 2.33(t, 2H, J=7.2 Hz), 2.05(t, 2H, J=7.2 Hz), 1.50(m, 4H), 1.22(m, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].[CH3:14][N:15]([CH3:17])[NH2:16]>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:17])[NH:16][C:12]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:13]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CN(C)N
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1NC(=O)NN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 300 mL of toluene containing 50 g of 2-methoxycarbonylphenyl isocyanate at 0° C. under a nitrogen atmosphere was added dropwise 21.44 mL of 1,1-dimethylhydrazine. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was then cooled to approximately 0° C., filtered, and the solid was rinsed with hexane to give 61.5 g of the title compound of Step A as a white solid.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[CH2:12]([NH:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.N>O.CO>[NH2:6][C:5]1[N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:20]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCc1ccccc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.43 g (21 mmol) of benzylhydrazine hydrochloride with a purity of 97% by weight, 1.4 ml of water, 6 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for 3 hours. After completion of the reaction, 5 ml of water was added to the mixture to cool the mixture up to 10° C. Then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 5 ml of cold water and dried under reduced pressure to obtain 3.89 g of 5-amino-1-benzyl-4-nitrosopyrazole (Isolation yield: 82.8%) as brown solid with a purity of 86.1% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 200 mg, 0.58 mmol) in DMSO (2 ml) in sealed tube, was added pyrrolidine (0.073 ml, 0.89 mmol), K2CO3 (153 mg, 1.11 mmol) and the mixture was stirred at 90° C. for 3 h. After cooling, the crude mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 10% ethyl acetate in hexane) to obtain 6-chloro-4-phenyl-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid ethyl ester (150 mg, 68%) as pale yellow solid. LC-MS: 381 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=O)[CH3:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:34][OH:35].[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[N:34][OH:35])[CH3:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1)=NO

Procedure:
630 mg (1 mM) of 1-(2-(bis-(4-fluorophenyl)-methoxy)-ethyl)-4 -(3-ketobutyl)piperazine (prepared as described in example 19) was suspended in 2 5 ml of ethanol at room temperature. A solution of hydroxylamine hydrochloride in 1 ml of water was added, followed by the dropwise addition of 240 mg of potassium hydroxide dissolved in 1 ml of water. The mixture was heated at reflux for 1 h, the solvent was evaporated, and the residue was dissolved by the addition of 5 ml of water and 5 ml of methylene chloride. The aqueous phase was extracted three times with methylene chloride, and the organic extract was washed with water, dried, and evaporated in vacuo. The residual oil was dissolved in ethanol, and a crude dimaleate salt was precipitated by addition of an ethanolic solution of 417 mg of maleic acid. The crude salt (405 mg) was recrystallized from 50 ml of hot ethanol to yield the dimaleate salt of the title compound as colourless crystals, melting at 161°-162° C. Analytical data were in accordance with the proposed structure. H-NMR spectrum indicated the presence of two stereoisomers in the ratio of 2.5:1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]=O)=[CH:27][CH:28]=1.Cl>C(O)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]=[C:6]2[C:5](=[O:20])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[O:8][CH:7]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(C2CC(=O)c3cc(O)ccc3O2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=C2C(=O)c3cc(O)ccc3OC2c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
A hot solution of 27 g of 6-hydroxy-4'-methoxyflavanone and 13.6 g of anisaldehyde in 1,400 ml of ethanol is saturated with HCl and is left for 3 hours to cool; precipitation with water gives 3-p-methoxybenzylidene-6-hydroxy-4'-methoxyflavanone, m.p. 199°-201°.
Reaction SMILES: [Cl-].[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]#[N:19].Cl>C(Cl)Cl>[C:2]([C:16]1[N:12]([CH3:11])[C:13]([CH2:17][C:18]#[N:19])=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a chilled suspension of 9.7 g. (0.07 mole) of alumonum chloride in 45 ml. methylene chloride is added 9 ml. (0.07 mole) benzoyl chloride. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 30 ml. methylene chloride while cooling externally with an ammonium chloride ice bath (temperature below 5° C.). After the addition is complete, the reaction mixture is stirred at 0° C. for fifteen minutes and then poured into ice acidified with 3N hydrochloric acid. The acidic fraction is extracted three times with methylene chloride. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine and 3N hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated off to yield an oily residue which is column chromatographed on neutral alumina using hexane, benzene and ethylacetate as successive solvents. The first few fractions having ultraviolet absorption in the 240-260 mμ range contain the desired product. These fractions are combined, the solvent evaporated off, and the oily residue, when triturated with methanol, yields the crystalline product, 5-benzoyl-1-methylpyrrole-2-acetonitrile, m.p. 106-108° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCc1cc2ccccc2o1
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: O=C(O)c1ccncc1NCc1cc2ccccc2o1
Yield: 3 %

Procedure:
The title compound was prepared in 3% yield from (1-benzofuran-2-ylmethyl)amine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.44 (br s, 1H), 8.39 (s, 1H), 7.97 (br s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.52-7.60 (m, 3H), 7.19-7.29 (m, 2H), 6.81 (s, 1H), 4.79 (s, 2H). [M+H] calc'd for C15H12N2O3, 269. Found 269.
Reaction SMILES: [NH2:1][C:2](=[N:21][OH:22])[C:3]1[CH:4]=[CH:5][C:6]([F:20])=[C:7]([CH:19]=1)[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37](O)=O)=[CH:33][C:32]=1[CH2:40][O:41][CH3:42])[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:22][N:21]=[C:2]([C:3]3[CH:4]=[CH:5][C:6]([F:20])=[C:7]([CH:19]=3)[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:1]=2)=[CH:33][C:32]=1[CH2:40][O:41][CH3:42])[CH3:24]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc(F)c(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1COC

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 60 (256.87 mg; 0.83 mmol) and Intermediate 36 (202.74 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a pale yellow oil. 1H NMR (CDCl3) δ 8.42 (d, J=1.4 Hz, 1H), 8.26 (dd, J=7.0, 2.1 Hz, 1H), 8.18-8.09 (m, 2H), 7.41-7.34 (m, 3H), 7.29-7.23 (m, 1H), 7.19 (t, J=9.0 Hz, 1H), 7.12-7.10 (m, 1H), 4.27-4.17 (m, 2H), 3.90 (s, 2H), 3.38 (s, 3H), 3.28 (s, 2H), 2.47-2.29 (m, 5H), 1.51 (s, 9H), 1.05 (t, J=7.5 Hz, 3H). LC/MS (Method B): 546.3 (M+H)+. HPLC (Method A) Rt 5.04 min (Purity: 99.5%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13])=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[Cl:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:25][CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: O=C(CCl)Nc1c(Cl)cccc1Cl
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNCC(=O)Nc2c(Cl)cccc2Cl)cc1OC

Procedure:
In a manner similar to Preparation 12, react 2-chloro-N-(2,6-dichlorophenyl)acetamide with 3,4-dimethoxybenzenemethanamine to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:22]([O-])([OH:24])=[O:23].O.[OH-].[Na+]>CCOCC>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Ethyl α -hydroxy-γ-(4-cyclohexylphenyl)butyrate 0.066 mole is added to ice-cold concentrated sulfuric acid (18 ml.) and stirred with cooling for 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml.) is added dropwise, maintaining the temperature between 30° and 40° by water cooling if necessary. After addition of the nitric acid is complete, the mixture is stirred for 1/2 hour, then poured into water. The mixture is made alkaline with sodium hydroxide, then ex-racted with ether. The ether extract is washed, dried over sodium sulfate, evaporated and the residue is fractionally distilled to obtain ethyl α-hydroxy-γ-(3-nitro-4-cyclohexylphenyl)butyrate.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:16][S-:17].[Na+]>C1COCC1.CCOCC>[CH3:16][S:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (4.8 g, 16.8 mmol) from Step 1 of Example 2 in THF (100 mL) was added sodium thiomethoxide (1.74 g, 25.2 mmol) slowly at 0° C. The reaction mixture was stirred at rt overnight. The mixture was diluted with Et2O (200 mL) and washed with saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate as a white solid (4.18 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J=1.5 Hz, 1H), 8.11 (dd, J=1.6, 8.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.82 (s, 3H), 1.42 (t, J=7.1 Hz, 3H) LCMS (ESI) m/z 254 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.O.O.O.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:15]1[CH:16]=[N:17][C:13]([CH3:12])=[N:14]1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Yield: 36.4 %

Procedure:
3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), 3-methyl-1H-1,2,4-triazole (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in 1 dimethyl sulfoxide (5 mL) were stirred for 6 hours at 70° C. The mixture was concentrated in vacuo; the residue was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried over magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (261 mg, 36%) as white crystals MS ISP (m/e): 223.3[(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.72 (d, 1H), 8.20 (m, 3H), 2.52 (s, 3H). Mp 105-107° C.