Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][NH2:8])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][NH:8][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C=CCOCC(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOCC(O)CNC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Allyloxy-2-hydroxy-propylamine made in Example 8 (110 g, 0.84 mol), triethylamine (85.6 g, 0.84 mol), and methylene chloride (300 mL) were mixed in a two-liter, two-neck flask, which was placed in an ice bath. To the above mixture, methacryloyl chloride (90.36 g, 84 mol) was added dropwise through an additional funnel at 0° C. After completion of the addition of methacryloyl chloride, the whole mixture was allowed to warm up to room temperature and stirred at ambient temperature overnight (˜15 hours). The reaction suspension was diluted with 250 mL of methylene chloride and washed with 5% aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, 5% aqueous sodium chloride solution and then followed by washing with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate (100 g). After the removal of sodium sulfate by filtration, 4-methoxyphenol (0.5 g) was added to the filtrate. The solution was concentrated under vacuum using a rotovap to give about 122 g of crude N-(3-allyloxy-2-hydroxy-propyl)-2-methyl acrylamide. N-(3-Allyloxy-2-hydroxy-propyl)-2-methyl acrylamide was purified by distilling the raw material inhibited with 1% of 4-methoxyphenol under vacuum at 168° C.–170° C. (7-8 mbar) using Kugelrohr distillation equipment.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]([CH3:23])[C:34]([NH:33][S:30]([C:27]3[CH:26]=[CH:25][C:24]([CH3:36])=[CH:29][CH:28]=3)(=[O:31])=[O:32])=[O:35])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
To a solution of N-{2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}-N-methylamine (step 1, 523 mg, 1.7 mmol) in dichloromethane (10 mL) and triethylamine (2 mL) was added p-toluenesulfonyl isocyanate (400 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford 358 mg (42%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.93 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.4 Hz), 6.92 (1H, s), 3.66-3.49 (2H, m), 3.51 (3H, s), 2.93-2.70 (4H, m), 2.65 (3H, s), 2.50 (3H, s), 2.38 (3H, s), 1.24 (3H, t, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCSc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1ccncc1
Temperature: 90 °C
Yield: 2.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 4-(2-chloroethylthio)pyridine hydrochloride (252 mg, 1.2 mmol) and potassium carbonate (454 mg, 3.3 mmol) in NMP (30 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol mixtures (100/0 increasing to 75/25) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)quinazoline (13 mg, 3%). m.p. 182-186° C. 1H NMR Spectrum: (DMSOd6) 3.58(t, 2H); 3.90(s, 3H); 4.40(t, 2H); 7.20(s, 1H); 7.32(d, 1H); 7.40(d, 2H); 7.50-7.60(m, 2H); 7.80(s, 1H); 8.32(s, 1H); 8.38(d, 2H); 9.57(s, 1H) MS-ESI: 457 [MH]+
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Cc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(OS(=O)(=O)c2ccc(I)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-Iodobenzenesulfonyl chloride (604 g, 2 mol) was added with stirring to a solution of 4-methylphenol (227 g, 2.1 mol) and triethylamine (222 g, 2.2 mol) in toluene (1.5 l). The suspension was stirred at 60° C. for 2 h. The reaction mixture was added to excess dilute hydrochloric acid. The precipitate was filtered off and washed with ethanol. A second crop was obtained by concentrating the toluene mother liquor and collecting the solid material in the same manner. The combined crops were recrystallized from 2-propanol (2.5 l). Yield 680 g, 91%.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].O.[OH-].[Li+].S(OC)(O[CH3:18])=O>O1CCCC1>[Br:1][C:2]1[C:3]([O:11][CH3:18])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Reactant: COS(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(C#N)cc1Br
Temperature: 75 °C
Yield: 83.9 %

Procedure:
To a solution 5-bromo-2-chloro-4-hydroxybenzonitrile (2, 29 g, 124 mmol) in tetrahydrofuran (500 mL) was added lithium hydroxide monohydrate (6.7 g, 161 mmol) and dimethyl sulfite (15.2 mL, 161 mmol). The resulting mixture was heated at 75° C. for 5 h, re-cooled to room temperature, and quenched with water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified on Biotage® purification apparatus (silica gel, 3 to 10% ethyl acetate in hexanes) to yield the title compound (26 g, 104 mmol, 85%) as a white solid.
Reaction SMILES: [OH-].[NH4+:2].F[C:4]1[C:9]([F:10])=[C:8]([F:11])[N:7]=[C:6]([C:12]#[N:13])[CH:5]=1>>[NH2:2][C:4]1[C:9]([F:10])=[C:8]([F:11])[N:7]=[C:6]([C:12]#[N:13])[CH:5]=1
Reactant: [NH4+]
Reactant: N#Cc1cc(F)c(F)c(F)n1
Agent: [OH-]
Product: N#Cc1cc(N)c(F)c(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
Ammonium hydroxide (NH4OH) was added to crude 4,5,6-trifluoropicolinonitrile (2.5 g, 15.8 mmol) and stirred at room temperature for 2 h. A brown solid formed which was filtered, washed with water and dried to give 0.72 g. Analysis by gas chromatography-mass spectroscopy (GC-MS) indicated the presence of two isomeric products. The aqueous filtrate was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated to give additional brown solid. The two crops were combined and purified by silica gel chromatography to give 4-amino-5,6-difluoro-picolinonitrile (0.60 g, 24.4%): 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J=5.3 Hz, 1H, aromatic), 6.62 (s, 2H, NH2); 13C NMR (101 MHz, CDCl3) δ 157.0 (dd, J=235, 12 Hz), 151.7 (dd, J=10, 7 Hz), 139.5 (dd, J=254, 29 Hz), 128.8 (d, J=19 Hz), 121.2 (s), 121.0 (s); 19F NMR (376 MHz, CDCl3) δ −85.29 (d, J=24.5 Hz), −156.98 (dd, J=24.5, 5.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14](N)=[O:15]>O>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:6]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: NC(N)=O
Solvent: O
Product: COc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Temperature: 200 °C
Yield: 88.8 %

Procedure:
A mixture of 2-amino-5-methoxybenzoic acid (5.00 g, 29.9 mmol) and urea (5.40 g, 90.0 mmol) was heated to 200° C. for 1 hour. The mixture was cooled to room temperature and diluted with H2O (50 mL), the mixture was filtered off and the precipitate was washed with H2O (10 mL), dried in vacuo to give the product (5.10 g, yield 88%).
Reaction SMILES: C[Si](C)(C)Cl.[CH3:6][C:7]([N+:13]([O-:15])=[O:14])([CH3:12])[CH2:8][CH2:9][CH2:10]O.[I-:16].[Na+]>C(#N)C>[I:16][CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([N+:13]([O-:15])=[O:14])[CH3:6]
Reactant: [I-]
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(CCCI)[N+](=O)[O-]

Procedure:
70 mL (0.544 mol) trimethylchlorosilane are added dropwise at ambient temperature to 40 g (0.272 mol) 4-methyl-4-nitro-pentan-1-ol and 81.5 g (0.544 mol) sodium iodide in 350 mL acetonitrile. The reaction mixture is filtered, evaporated down and combined with diethyl ether. The organic phase is washed with sodium bisulphite solution and water, dried and freed from the solvent. Yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[N:11][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]=[CH:3]1.[BH4-].[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[N:11][C:6]=2[S:5](=[O:14])(=[O:13])[NH:4][CH2:3]1
Reactant: Cc1cnc2c(c1)N(C)C=NS2(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(c1)N(C)CNS2(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of 0.5 g of 4,6-dimethyl-4H- pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 76) in 25 cm3 of a 1/1 isopropanol/chloroform mixture is treated, in small portions, with 0.4 g of sodium borohydride with good stirring and under an inert atmosphere. After 30 minutes at ambient temperature, the excess borohydride is destroyed by addition of a few drops of acetic acid and the solvent is removed under reduced pressure. The residue is taken up in 10 cm3 of water and the pH of the mixture is brought to neutrality. The precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([N+:21]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[C:6]([NH2:21])[CH:5]=1
Reactant: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)c(N)c1
Yield: 88.6 %

Procedure:
3-Amino-4-(2-tert-butoxycarbonylamino-ethylamino)-benzoic acid methyl ester (525.0 mg) was prepared by following General Procedure B starting from 4-(2-tert-butoxycarbonylamino-ethylamino)-3-nitro-benzoic acid methyl ester (650.0 mg) and Pd/C (20% by weight, 130.0 mg) in MeOH:EtOAc (1:1, 6.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][OH:26])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][O:26][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CCCN(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 83 (0.138 g, 0.319 mmol, 1 equiv) in CH2Cl2 (3 mL) was cooled to 0° C. prior to sequential addition of Et3N (0.222 mL, 1.59 mmol, 5 equiv) and CH3SO2Cl (0.049 mL, 0.637 mmol, 2 equiv). The cooling bath was removed after 5 min and the mixture was stirred at 25° C. for 1 h. The reaction was quenched with the addition of saturated aqueous NaHCO3 (0.5 mL) and the layers were separated. The aqueous portion was extracted with EtOAc (2×5 mL) and the combined organic portions were dried (MgSO4), filtered, and concentrated. Radial chromatography (SiO2, 2 mm plate, 30% EtOAc-hexane) furnished 84 (0.143 g, 0.163 g theoretical, 89%) as a white solid: mp 134-135° C.; 1H NMR 400 MHz, CDCl3) major rotamer δ 8.40 (d, 8.2 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.60-7.35 (m, 7H), 6.63 (s, 1H), 5.26 (d, J=11.7 Hz, 1H), 5.17 (d, J=11.6 Hz, 1H), 4.49-4.44 (m, 2H), 4.38-4.30 (m, 2H), 2.69-2.64 (m, 4H), 2.26-2.05 (m, 2H), 1.73-1.70 (m, 2H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) major rotamer δ 153.8, 153.6, 140.5, 136.7, 133.0, 128.8 (2C), 128.6, 128.1 (2C), 127.7, 127.6, 127.1, 125.2, 123.3, 122.8, 107.1, 80.8, 71.4, 70.2, 47.7, 37.1, 36.1, 28.3 (3C), 26.5, 24.4; IR (film) νmax 3056, 2974, 2933, 2862, 1692, 1615, 1590 cm−1; FABHRMS (NBA-NaI) m/z 534.1914 (M+Na+, C28H33NO6S requires 534.1926).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Si:20]([O:27][CH2:28][CH:29]([OH:40])[C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:40][CH:29]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH2:28][O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (0.5 g, 2.27 mmol) in DMP (10 ml) were added anhydrous cesium carbonate (0.74 g, 2.27 mmol) and 1-tert-butyldimethylsilyloxy 2-hydroxy 2-(4-tertbutylphenyl)ethane (0.7 g, 2.27 mmol). The mixture is stirred for 2 hours at 70° C. and then cooled to room temperature and ethyl acetate is added to it. The solution is then washed with water, dried and concentrated and the residue subjected to purification by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above compound.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH:14]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([CH3:16])[CH3:15]>>[CH:14]([N:17]1[CH2:22][CH2:21][C:20]2[NH:2][C:4]3[C:13]([C:19]=2[CH2:18]1)=[C:8]1[C:9]([CH3:12])=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)([CH3:16])[CH3:15]
Reactant: Cc1csc2ccc(NN)cc12
Reactant: CC(C)N1CCC(=O)CC1
Agent: Cl
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(C(C)C)CC4

Procedure:
The compound is formed analogously to that described in Example 15, from 11 g of 5-hydrazino-3-methylbenzothiophene hydrochloride and 10 g of 1-isopropyl-4-piperidone. Melting point: 199°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]3OCC[O:22]3)[CH:15]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:26].Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:15]=2)[CH:21]=[O:22])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:26]
Reactant: Cc1cc([C@H](Nc2ccc(C)c(C3OCCO3)c2)C(F)(F)F)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc([C@H](Nc2ccc(C)c(C=O)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
To a solution of acetal INT 32 (4.91 g, 12.73 mmol) in THF (127 mL) at 0° C. was added HCl (2 M in H2O, 25.5 mL, 50.92 mmol). The reaction mixture was stirred at room temperature for 100 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 (2×), water (2×) and brine (1×). The organic layer was dried over MgSO4, filtered and concentrated to give INT 33.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:25][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][C:35](=[O:37])[CH3:36])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH2:17][NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:21])=[O:20]
Reactant: CC(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 38.9 %

Procedure:
The title compound (108 mg, 39%, slow crystallizing foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and acetyl chloride (0.05 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:9]([C:10]2[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([C:18](=[NH:26])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:8][C:7]([C:27](=[NH:35])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1>O.Cl>[ClH:1].[OH:16][C:15]1[C:10]([C:9]2[C:4]([OH:3])=[CH:5][CH:6]=[C:7]([C:27](=[NH:35])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:8]=2)=[CH:11][C:12]([C:18](=[NH:26])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=N)Nc2ccccc2)cc1-c1cc(C(=N)Nc2ccccc2)ccc1OC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(Nc1ccccc1)c1ccc(O)c(-c2cc(C(=N)Nc3ccccc3)ccc2O)c1
Temperature: 180 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
A mixture of 2.5 g of 6,6'-dimethoxy-N,N"-diphenyl[1,1'-biphenyl]-3,3'-dicarboximidamide, monohydrochloride (see Example 1) and 25 g of dry pyridine hydrochloride is heated at 180° C for 75 minutes. The mixture is then cooled, diluted with 10 ml of water and acidified with 10 ml of concentrated hydrochloric acid. The mixture is further diluted with 100 ml of 10% hydrochloric acid and allowed to stand at 0° C for about 16 hours. The crystalline material so obtained is recrystallized from dilute HCl (10% hydrochloric acid and water until solution occurs at 100° C) to yield 900 mg of the title compound, melting point 306°-307° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22])([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(O)c(N)c1

Procedure:
To a solution of 310 g of acetic acid and 262 g (1 mole) of 4-dodecyl phenol maintained at 20° C. is slowly added with stirring 76 ml (1.2 moles) of HNO3 in 40 ml of water. After 30 minutes, ice water (800 ml) is added to the reaction vessel and the resulting mixture is extracted with methylene chloride. The methylene chloride phase is withdrawn and washed successively with water, an aqueous solution of NaHCO3 (5 percent) and water. The methylene chloride is then removed under vacuum to obtain the desired 2-nitro-4-dodecylphenol. A solution of 46 g (0.15 mole) of the nitrated phenol, 550 ml of absolute ethanol and 1.2 g of platinum oxide is maintained at 20° C. under 50 psi of hydrogen for 23 hours. The reaction mixture is filtered and then subjected to vacuum to remove solvent. Essentially quantitative yield of the desired 2-amino-4-dodecylphenol is recovered. A solution of 200 ml of acetone, 200 ml of water and 38.8 g (0.14 mole) of the amino phenol is stirred with 200 ml of a carbonate form (CO3=) quaternary ammonium styrene/divinyl benzene, ion exchange resin sold by The Dow Chemical Company under the trade name, Dowex® SBR, forty-nine ml (0.787 mole) of methyl iodide is added to the aforementioned solution through a dry ice condenser. After refluxing the reaction mixture with stirring for 20 hours, the mixture is filtered and excess methyl iodide is removed under vacuum. The resulting solution is contacted with the hydroxide form of the aforementioned ion exchange resin to provide the desired quaternary ammonium zwitterion.
Reaction SMILES: [CH3:1][SiH:2]([CH3:10])[N:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[CH:4]([N:3]1[CH2:7][CH2:8][CH2:9][Si:2]1([CH3:10])[CH3:1])=[CH:5][CH3:6]
Reactant: C=CCN(CC=C)[SiH](C)C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC=CN1CCC[Si]1(C)C
Temperature: 80 °C
Yield: 98 %

Procedure:
Into a glass tube with an outside diameter of 10 mm and a length of 10 cm were introduced 2 mg RhCl(PPh3)3 and 2 mL of a mixture of 1 part N-dimethylsilyldiallylamine and 3 parts benzene, and the tube was sealed. After heating this for 17 hours at 80° C., the conversion was 100 weight % and 1-propenyl -2,2-dimethyl-1-aza-2-silacyclopentane was obtained in a yield of 98%. No production of 1-allyl-2,2,3-trimethyl-1-aza-2-silacyclobutane was observed.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:10]([C:11](=[O:13])[CH3:12])=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:7]3[N:8]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2C(C)=O)cc1
Reactant: C1CCNC1
Product: COc1ccc(-c2nn3c(N4CCCC4)cccc3c2C(C)=O)cc1
Yield: 84 %

Procedure:
In a similar manner as described in Example 1 from 1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (5.00 g, 16.6 mmol) and pyrrolidine, 1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (4.68 g, 84%) was obtained as a yellow crystalline solid. 1H NMR (CDCl3): δ 7.79 (d, 1H), 7.50 (dd, 2H), 7.33 (t, 1H), 6.97 (dd, 2H), 6.12 (d, 1H), 3.84 (s, 3H), 3.74–3.70 (m, 4H), 2.11 (s, 3H), 1.99–1.95 (m, 4H); MS m/z 336 (M+1).