Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:32]([C:27]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=3)(=[O:34])=[O:33])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc12
Yield: 43.4 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide can be obtained as described in Example 1 from 1 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 50 ml of tetrahydrofuran, 1.15 ml of triethylamine and 1.1 g of 3,4-dichlorobenzenesulfonyl chloride. 0.8 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide is thus obtained in the form of a white solid melting at 171° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:29]CC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:12]([OH:29])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(-c3ccccc3)c2)CC1
Reactant: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of the title A compound, 4-biphenyl-3-yl-3,6,dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.57 g, 7.66 mmol) and 6 mL of dry THF is added dropwise under argon at 5° C. a 1M borane-tetrahydrofuran complex solution (11 mL, 11 mmol) within 15 min. The reaction mixture is stirred for 10 min. at 5° C. and for 1 h at RT. NaBO3 (3.38 g, 22 mmol) is then added in several portions followed by H2O (10 mL). After 2 h at RT, the reaction mixture is extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid t-butyl ester as a white amorphous solid: MS (after treatment with trifluoroacetic acid) 254.3 [M+H—C5H8O2]+; Rf 0.10 (hexane/ethyl acetate 8:2).
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:7]1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:14][CH3:15])[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH3:13]
Reactant: CCC(O)(CC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCC1(CC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (7.0 mL) was added dropwise to 3-(2,2′-bithiophene-3-yl)pentan-3-ol (IIa) (2.67 g, 11 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (100 mL) and water (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford pure dark yellow oil (Ia) (1.2 g, 47%). 1H-NMR (CDCl3): δ=7.21 (d, J=4.8 Hz, 2H), 7.00 (d, J=4.8 Hz, 2H), 1.98 (q, J=6.8 Hz), 4H), 0.70 (t, J=7.0 Hz, 6H). 13C-NMR (CDCl3): δ=157.89, 137.36, 125.09, 122.16, 54.76, 30.71, 9.74.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([O:28][CH3:29])[CH:6]=1)(=O)C.[OH-].[K+]>C(O)C>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20]2)=[O:14])=[C:7]([O:28][CH3:29])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1NC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1NC(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
A solution of N-(4-acetylamino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide (e9) (1.4 g) in ethanol (20 ml) was refluxed for 1 hour with an aqueous (4 ml) solution of potassium hydroxide (0.6 g). The solvent was removed by evaporation and the residue extracted with ethyl acetate. Chromatography of the solution (on alumina with 5% water, in chloroform) followed by evaporation of the solvent yielded N-(4-amino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide (e10).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8](COCC[Si](C)(C)C)[CH:7]=2)=[N:2]1.[F:43][C:44]([F:48])([F:47])[CH2:45]I.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O.N>CN(C=O)C>[CH3:34][C:31]1[CH:32]=[CH:33][N:20]2[C:21]=1[C:22](=[O:30])[N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([C@@H:16]([NH:15][C:13]1[C:14]3[C:6]([C:3]4[CH:4]=[CH:5][N:1]([CH2:45][C:44]([F:48])([F:47])[F:43])[N:2]=4)=[CH:7][NH:8][C:9]=3[N:10]=[CH:11][N:12]=1)[CH3:17])=[N:19]2
Reactant: FC(F)(F)CI
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(CC(F)(F)F)n5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.07 mmol) and 1,1,1-trifluoro-2-iodoethane (36 mg, 0.17 mmol) were dissolved in DMF (2 ml) and cesium carbonate (140 mg, 0.43 mmol) was added. After stirring the mixture at 80° C. for 2 h, the solvent was evaporated under reduced pressure and the residue was suspended in water and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue (54 mg) was treated with trifluoroacetic acid (1 mL, 13 mmol) and a solution of ammonia (7N in methanol, 10 ml, 70 mmol) according to the method described in Example 27 to give 4.6 mg (12% yield) of the title compound. Purity 93%.
Reaction SMILES: CC[O-].[Na+].S(O)(O)(=O)=O.[CH3:10][O:11][C:12]([NH2:14])=[NH:13].C[CH2:16][CH:17]([C:22](OCC)=[O:23])[C:18](OC)=[O:19]>C(O)C>[CH3:10][O:11][C:12]1[N:14]=[C:18]([OH:19])[C:17]([CH3:16])=[C:22]([OH:23])[N:13]=1
Reactant: COC(=N)N
Reactant: CCOC(=O)C(CC)C(=O)OC
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
13.8 g (200 mmoles) of sodium ethylate is added to a solution of 10 g (58 mmoles) of methoxyformamidine sulphate in 100 ml of ethanol cooled down to 0° C. and the mixture is stirred for 15 minutes; then a solution of 9 ml (52 mmoles) of diethyl methyl malonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phases are dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). 5.9 g of expected product is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:35]([F:38])([F:37])[F:36])[CH:6]=[C:7]([NH:9][C:10](=[O:34])[N:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:12])[CH:8]=1.C([O-])(O)=O.[Na+].C(Cl)[Cl:45]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:35]([F:37])([F:38])[F:36])[CH:6]=[C:7]([NH:9][C:10](=[O:34])[N:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)=[C:22]([Cl:45])[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:12])[CH:8]=1
Reactant: ClCCl
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)cc(C(F)(F)F)c4)ncn3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)cc(C(F)(F)F)c4)ncn3)cc2Cl)CC1
Temperature: 0 °C

Procedure:
Portions of 0.4 mL of a 1 M solution of SO2Cl2 in DCM are added repeatedly over a period of 27 h to an ice-cooled suspension of 3-(5-methoxy-3-trifluoromethyl-phenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (105 mg, 0.20 mmol) (Example 26) in acetonitrile (6 mL). The reaction is followed by HPLC analysis. The reaction mixture (still containing starting material) is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with brine, dried (Na2SO4), filtered and concentrated. Reversed phase MPLC (H2O/CH3CN+0.1% TFA) yields, after neutralization of the product containing fractions with NaHCO3, partial concentration and extraction with DCM, the title compound: API-MS: 564/566 [MH]+; TLC: Rf=0.28 (DCM/MeOH+1% NH3aq, 95:5); 1H-NMR (DMSO-d6) δ 1.02 (t, H3C), 2.37 (q, H2C), 2.51 (m, 4H), 2.92 (m, 4H), 3.33 (s, H3C), 3.82 (s, H3C), 6.48 (s, 1H), 6.90 (s, 1H), 7.12 (d, 1H), 7.43 (m, 2H), 7.59 (s, 1H), 7.82 (s, 1H), 8.55 (s, 1H), 9.66 (s, HN), 12.33 (s, HN).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)[nH]c1=O
Yield: 56.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (280 mg, yield: 56.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[N:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:36]1[N:28]2[C:27]([CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29]2)=[CH:38][CH:37]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine. The mixture is stirred at room temperature for 5 hours and is then washed with water, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 142°-146° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccccc1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH:15]=[CH:14][O:13][C:12]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[H][H]>CO.[Pt](=O)=O>[N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH2:15][CH2:14][O:13][C:12]=23)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: c1cc2ccoc2c(N2CCNCC2)n1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: c1cc2c(c(N3CCNCC3)n1)OCC2
Yield: 95.1 %

Procedure:
A mixture of 7-(piperazin-1-yl)-furo[2,3-c]pyridine [CAS-No. 209160-83-8] (1 g, 4.92 mmol), platinum(IV) oxide (0.46 g, 4.32 mmol), acetic acid (2.3 ml) in MeOH (6.9 ml) was stirred in a hydrogen atmosphere at room temperature for 24 h. After removal of the catalyst by filtration the mixture was evaporated, the residue was dissolved in dichloromethane (70 ml), washed with 2N sodium carbonate solution (40 ml), dried (MgSO4) and evaporated to yield 7-(piperazin-1-yl)-2,3-dihydro-furo[2,3-c]pyridine as a light brown oil (0.96 g, 95%), MS (ISP) m/z=206.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH:8]([OH:22])[CH2:9][N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:22][CH:8]([CH2:9][N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)CN(CC(O)COc1ccc(Cl)cc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CN(CC(COc1ccc(Cl)cc1)OC(C)=O)c1ccccc1
Reaction time: 20 h
Yield: 82.9 %

Procedure:
After 5.5 g (0.0157 moles) of 1-(p-chlorophenoxy)-3-(N-carbomethoxymethyl-N-phenylamino)-2-propanol and 6.0 g (0.059 moles) of acetic anhydride were dissolved in 30 ml of pyridine and left to stand at the room temperature for 20 hr, the reaction mixture was concentrated. The resulting residue was poured into iced water to afford precipitates. The precipitates were collected by filtration, washed with water and dried. Recrystallization from isopropanol gave 5.1 g (83%) of the crystals, m.p. 82°-83.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1.F[B-](F)(F)F.[O:25]=[N+:26]=[O:27].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:18][CH3:19])[C:17]([N+:26]([O-:27])=[O:25])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1cc2cccc(-c3ccc(Cl)cc3Cl)n2n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 35.6 %

Procedure:
After dissolving 7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine (280 mg) in acetonitrile (20 mL), nitronium tetrafluoroborate (255 mg) was added 4 times at 30 minute intervals while stirring on ice. The reaction mixture was added to ice water, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (115 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].ClC1C=C(C=CC=1)C(O[CH:14]1[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1)=O>C(#N)C>[NH2:5][CH:14]1[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1
Reactant: [NH4+]
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC1=C(c2ccncc2)SC(N)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
Ammonium carbonate (0.6 g) was added to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.4 g) in acetonitrile (20 ml). The mixture was stirred at ambient temperature for 3 days, was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=20:1) as an eluant to give the titled compound (0.1 g, yield 40.7%).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:14]([C:19](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:20])([O:16][CH2:17][CH3:18])=[O:15].C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:19]([CH3:20])=[CH:12][CH:9]1[CH2:8][CH2:7][CH:6]([C:1]([CH2:4][CH3:5])([CH3:2])[CH3:3])[CH2:11][CH2:10]1)[CH3:18]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)(C)C1CCC(C=O)CC1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)=CC1CCC(C(C)(C)CC)CC1

Procedure:
A mixture of 46.3 g of 4-tert.amyl-cyclohexane-1-carboxaldehyde, 92.3 g of (α-carbethoxy-ethylidene)-triphenyl-phosphorane and 7.6 g of benzoic acid in 250 ml of toluene is heated at reflux for 3.5 hours under nirogen gasification and the toluene is evaporated. The oily-crystalline residue is dissolved in 1600 ml of methanol/water (4:1) and exhaustively extracted with hexane. The combined hexane extracts are washed with sodium carbonate solution and water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3-(4-tert.amyl-cyclohexyl)-2-methyl-acrylic acid ethyl ester of boiling point 113°-115° C./0.03 Torr.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([C:10]2[S:14][C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:17])=[N:12][C:11]=2[C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCOCC1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:11]1[N:12]=[C:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:17])[S:14][C:10]=1[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:7]=1)=[O:9]
Reactant: C1COCCN1
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)c2cccc(Br)n2)s1)c1ccncc1
Solvent: C1COCCO1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2cccc(N3CCOCC3)n2)s1)c1ccncc1
Yield: 22.4 %

Procedure:
Compound 300 (133 mg, 0.300 mmol) was suspended in 1,4-dioxane (2 mL), and morpholine (0.525 mL, 6.00 mmol) was added thereto, followed by stirring under heating and reflux for 5 hours. The reaction mixture was purified through silica gel column chromatography (chloroform:methanol=9:1) to afford the entitled Compound 301 (31.0 mg, 23%) as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][N:30]([CH3:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:36])=[CH:33][CH:32]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(N(C)C)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(dimethylamino)benzoyl chloride: ESMS m/e: 527.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][CH2:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:6]
Reactant: O=C(O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: NCC(=O)NCC(F)(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CNC(=O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added carbonyldiimidazole (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[H-].[Na+].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O>[CH3:17][O:18][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6]
Reactant: CON(C)C(=O)c1cccc(O)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc(C(=O)N(C)OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
69.0 g (380 mmol) of B5 were dissolved in 500 ml of dry dimethylformamide, cooled to 0° C. and 11.5 g (480 mmol) sodium hydride were added and the mixture was allowed to stirr for 10 minutes. A solution of 31.2 ml (418 mmol) (chloromethyl)methylether in 100 ml of dry diemthylformamide was added at this temperature over a period of 30 minutes. After stirring at room temperature overnight, the solvent was distilled off and the residue was partitionated between 400 ml of dichloromethane and 100 ml of water. The organic layer was washed with 50 ml of aqueous sodium hydrogen carbonate and two times with water (80 ml each) and finally dried over sodium sulfate. Removing the solvent in vacuo yielded 73.5 g (87%) B6 as a colorless oil which was used without further purification.