Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][CH:34]1[C:41](=[O:42])[N:40]2[CH:35]1[S:36][CH2:37][C:38]([CH3:59])=[C:39]2[C:43]([O:45][CH:46]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>C(Cl)Cl>[CH:46]([O:45][C:43]([C:39]1[N:40]2[CH:35]([S:36][CH2:37][C:38]=1[CH3:59])[CH:34]([NH:33][C:27](=[O:29])[C:26](=[N:30][O:31][CH3:32])[C:24]1[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=1)[C:41]2=[O:42])=[O:44])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of the anhydride of 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetic acid (syn isomer)(7.2 g) in methylene chloride (22.5 cc) is added in a single shot to a solution of 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3.15 g) in methylene chloride (31.5 cc). The temperature rises from 8° to 14° C. The mixture is kept stirred for one hour 15 minutes, during which the temperature returns to 20° C., and is then washed with 0.5 N hydrochloric acid (10 cc), distilled water (10 cc) and a saturated sodium bicarbonate solution (20 cc). The insoluble matter formed is filtered off, and the organic phase is washed again with distilled water (two×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is chromatographed over a column (diameter: 3 cm, height: 33 cm) containing silica gel (125 g), and elution is carried out with ethyl acetate/cyclohexane mixtures (1.2 and 1 liter, of respective composition 20:80 and 40:60 by volume), 50 cc fractions of eluate being collected. Fractions 31 to 44 are evaporated and 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene, syn isomer (2.8 g) is obtained in the form of a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[C:11]([O:12][CH3:13])=[CH:10][S:9][C:8]=1[CH3:14])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:13][O:12][C:11]1[C:7]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:24](=[O:25])[CH2:23][Cl:22])=[C:8]([CH3:14])[S:9][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: CCOCCNc1c(OC)csc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOCCN(C(=O)CCl)c1c(OC)csc1C

Procedure:
To a well stirred mixture of 6,05 g (0.03 mol) N-(2-ethoxyethyl)-4-methoxy-2-methyl-thiophene-3-amine, 4.15 g (0.03 mol) of K2CO3, 10 ml of water and 100 ml of CH2Cl2 is added dropwise without cooling the solution of 3.4 g (0.03 mol) of chloroacetyl chloride in 10 ml of CH2Cl2. After the exothermic reaction (27°) has subsided, stirring is continued for a further hour at ambient temperature.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:8]([CH3:21])[N:9]=[C:10]2[C:15]=1[C:14](=[O:16])[NH:13][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11]2.O1CCCC1>C(N(CC)CC)C>[CH3:21][N:8]1[C:7]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[C:15]2[C:10]([N:11]=[C:12]([C:17]([CH3:18])([CH3:20])[CH3:19])[NH:13][C:14]2=[O:16])=[N:9]1
Reactant: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N(S(C)(=O)=O)S(C)(=O)=O

Procedure:
Methanesulphonyl chloride (12.9 g) was added slowly to a stirred mixture of 3-amino-2-methyl-6-(1,1-dimethylethyl)-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (11 g) prepared as in Example 1, tetrahydrofuran (85 ml) and triethylamine (21 ml), causing the mixture to boil. The mixture was heated under reflux for 3 hours, and was then cooled and filtered. The filtrate was then evaporated to dryness, and the residue was washed with 80:20 ethanol/water to give the title compound, m.p. 258°-259° C.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CN=C1>O1CCCC1.C(OCC)C>[CH3:1][Si:2]([CH3:7])([C:3]([CH3:6])([CH3:5])[CH3:4])[O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Reaction time: 3 h

Procedure:
A solution of dimethyl-t-butylsilyl chloride (18 g.) in tetrahydrofuran (50 ml.) was added dropwise to a stirred solution of 8-bromooctanol (20 g.) and imidazole (14.2 g.) in tetrahydrofuran (100 ml.) and the mixture was stirred at laboratory temperature for 3 hours, diluted with diethyl ether (200 ml.) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using petroleum ether (b.p. 60°-80° C.) as eluant. A solution of the 8-(dimethyl-t-butylsilyloxy)octyl bromide thus obtained (6.46 g.) in dimethyl sulphoxide (2 ml.) was added to a stirred suspension of lithium acetylide-ethylenediamine complex (2.02 g.) in dimethylsulphoxide (30 ml ) which was cooled to 10° C.; and the mixture was stirred for 18 hours and then poured into ice-water (150 ml.). The mixture was extracted three times with petroleum ether (b.p. 60°-80° C.; 30 ml. each time) and the combined extracts were washed with water (10 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 5:1 v/v mixture of cyclohexane and diethyl ether as eluant. There was thus obtained 10-(dimethyl-t-butylsilyloxy)dec-1-yne.
Reaction SMILES: [CH:1]([Si:3]([CH3:11])([CH3:10])[O:4][Si](C=C)(C)C)=[CH2:2].[Cl:12][Si:13]([Cl:16])(Cl)[Cl:14].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:12][Si:13]([Cl:16])([Cl:14])[O:4][Si:3]([CH:1]=[CH2:2])([CH3:11])[CH3:10]
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: C=C[Si](C)(C)O[Si](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
A mixture containing 595 g (3.2 mol) of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane, 136 g (0.8 mol) of tetrachlorosilane and 2 ml of a 25% solution of phosphonitrile chloride in methylene chloride is stirred at room temperature for 8 hours. About 2.3 ml of tri-n-butylamine are then added to deactivate the phosphonitrile chloride. The reaction mixture is stirred for 30 minutes and then subjected to fractional distillation. About 216 g of 1,1,1-trichloro-3-vinyl-3,3-dimethyldisiloxane are obtained at 20° to 22° C. and at 2 mbar; about 53 g of 1,5-divinyl1,1,5,5-tetramethyl 3,3-dichlorotrisiloxane are obtained at 23° to 42° C. and at 2 mbar, and 9 g of a 1:1 mixture of 1,5divinyl-1,1,5,5-tetramethyl-3,3-dichlorotrisiloxane and 1,5-divinyl-1,1,5,5-tetramethyl-3-chloro-3-trimethylsiloxytrisiloxane are obtained at 42° to 72° C. and at 2 mbar. About 372 g of vinyldimethylchlorosilane are collected in the cold trap. The desired 1,5-divinyl-1,1,5,5-tetramethyl-3,3-bis(vinyldimethylsiloxy)trisiloxane is not obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24]C(=O)C2C=CC=CC=2)=[N:9]3)[S:6][CH:7]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:5]2[S:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=1
Reactant: N#Cc1csc(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1csc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(N)=N3)c1
Temperature: 25 °C

Procedure:
Racemic N-[7a-(4-cyano-2-thienyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.01 g, 2.17 mmol), pyridine (2.64 mL, 32.6 mmol), and O-methylhydroxylamine hydrochloride (1.82 g, 21.7 mmol) in ethanol (250 mL) are stirred at 60° C. for 24 hours. The mixture is cooled to ambient temperature and concentrated. The mixture is diluted with water and extracted with DCM followed by 3:1 chloroform:isopropyl alcohol. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated. The crude product is purified over silica gel using a gradient of hexane:ethyl acetate (1:0 to 0:1, over 30 min). The product is chirally separated by SFC (Column: Chiralpak AS-H 2.1×15 cm; 5μ; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 70 mL/minute at 225 nm). The first eluting isomer is the title compound (99% ee). Analysis column: Chiralpak AS-H 4.6×150 mm; eluent: 30% methyl alcohol with 0.2% isopropylamine) in CO2; flow: 5.0 mL/min at UV 225 nm, RT=1.08 minutes). ES/MS (m/e): 361 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:24]1CCOCC1.ClC(OCC(C)C)=O.N>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:11])[NH2:24])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid and N-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwise iso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at 0° C. for 20 minutes. after which NH3 (g) is passed through the reaction mixture for 30 minutes at 0° C. The reaction mixture is concentrated and the residue dissolved in EtOAc, washed successively with 5% citric acid, water, 5% NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to a residue that is triturated with a mixture of EtOAc/petroleum ether to provide 2.2 g (74% yield) of the desired product as a white solid.
Reaction SMILES: C(N1CCNC1=NC#N)C1C=CC=CC=1.[CH2:16]([N:23]1[CH2:27][CH2:26][NH:25][S:24]1(=[O:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[C:31]1[S:32][C:33]([C:37]([NH:39][CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[C:34]([CH3:36])[N:35]=1>>[CH2:16]([N:23]1[S:24](=[O:29])(=[O:28])[N:25]([C:31]2[S:32][C:33]([C:37]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:38])=[C:34]([CH3:36])[N:35]=2)[CH2:26][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Agent: N#CN=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)S2(=O)=O)sc1C(=O)NCc1cccnc1
Yield: 79 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 2-benzyl-1,2,5-thiadiazolidine 1,1-dioxide to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 79% yield: mp 140-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.8 Hz, 1H), 8.49-8.43 (m, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.39-7.28 (m, 6H), 4.37 (d, J=5.8 Hz, 2H), 4.26 (s, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.3, 157.2, 152.9, 149.3, 148.5, 135.6, 135.2, 129.6, 129.0, 128.8, 128.5, 124.0, 119.6, 51.3, 46.0, 44.7, 40.9, 17.5; MS (ES+) m/z 444.3 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[C:18]([O-])(=[O:20])C.[Na+]>CN(C)C=O>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:20])=[CH:10][CH:9]=1
Reactant: COc1cccc2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C=O)c2ccccc12

Procedure:
Phosphorus oxychloride (315 g, 1.6 mole) was added dropwise over 4 hours to a stirred solution of 1-methoxynaphthalene (250 g) (2) in dried dimethylformamide (150 g). the reaction mixture was heated on a water bath for a further 4 hours, cooled, and poured onto ice (1 k) and 2M aqueous sodium acetate (1.5 l). The organic layer was extracted with dichloromethane (1 l) and washed with dilute hydrochloric acid and then with water. The organic layer was dried (MgSO4), filtered, and the solvent removed. 4-Methoxy-1-naphthaldehyde (3) was obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:38]([NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:40])[CH3:39]
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 29.9 %

Procedure:
A solution of 4-[2-(4-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulphonamide (0.185 g 0.42 mmol), triethylamine (0.4 ml), 4-dimethylaminopyridine (0.024 g 0.18 mmol) and acetic anhydride (0.12 ml 1.2 mmol) in chloroform (10 ml) was stirred at room temperature for 4 hr. The reaction mixture was washed with 2M hydrochloric acid (10 ml), M Na2CO3 (5 ml) and water (10 ml). Drying (MgSO4) and removal of solvent gave the title compound as a white solid (0.06 g 31%).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[C:20]([N:25]([CH3:27])[CH3:26])([CH3:24])[CH2:21][CH:22]=[CH2:23])=[CH:15][CH:14]=1>CC(N(C)C)=O>[SH:4][CH2:3][CH2:2][CH2:1][S:5][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[C:20]([N:25]([CH3:27])[CH3:26])([CH3:24])[CH2:21][CH:22]=[CH2:23])=[CH:15][CH:14]=1
Reactant: C=CCC(C)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: SCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCC(C)(C(=O)c1ccc(SCCCS)cc1)N(C)C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
25.0 g (0.23 mol) of 1,3-propandithiol are dissolved in 80 ml of dry dimethylacetamide and 6.0 g of potassium carbonate are added. 10.0 g of 1-(4-fluorophenyl)-2-dimethylamino-2-methylpent-4-en-1-one in 20 ml of dry dimethylacetamide are added dropwise. The suspension is stirred at 50° C. for 12 h, the solid is filtered off. The excess 1,3-propanedithiol and dimethylacetamide are distilled off. To the residue toluene is added and the precipitate is filtered off. After toluene is distilled off, the residue is purified by column chromatography on silica gel with ethyl acetate-hexane (1:10) as eluent and an oily product is obtained. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.18 (s,3H), 1.39 (t,1H), 2.00 (m,2H), 2.27 (s,5H), 2.42 (m, 1H), 2.66-2.72 (m,3H), 3.12 (t,2H), 4.83-4.93 (m,2H), 5.52 (m, 1H), 7.26 (d,2H), 8.38 (d,2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.O.NN>COCCO>[NH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:30]=[CH:31][CH:32]=[C:4]([NH2:1])[CH:5]=3)=[CH:13][CH:12]=2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc(-c3ccc(Oc4cccc([N+](=O)[O-])c4)cc3)cc2)c1
Agent: NN
Solvent: O
Solvent: COCCO
Product: Nc1cccc(Oc2ccc(-c3ccc(Oc4cccc(N)c4)cc3)cc2)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In the next step, a 1 1 glass reaction vessel was charged with 100 grams (0.23 mol) of crude 4,4'-bis(3-nitrophenoxy)biphenyl, 10 grams of active carbon, 1 grams of ferric chloride hexahydrate and 500 ml of 2-methoxyethanol. The mixture was stirred for 30 minutes under reflux and then added dropwise with 46 grams (0.92 mol) of hydrazine hydrate during 3 hours at 70°-80° C. The reaction was terminated by stirring for 5 hours at 70°-80° C. after ending the dropwise addition. The reaction mixture was cooled, filtered to remove the catalyst and poured into 500 ml of water. The separated crystals were filtered, added with 48 grams of 35% hydrochloric acid and 540 ml of 50% isopropyl alcohol and warmed. The solution thus obtained was allowed to cool. The separated 4,4'-bis(3-aminophenoxy)biphenyl hydrochloride was filtered, added with 540 ml of 50% isopropyl alcohol and warmed. The solution thus obtained was added with 5 grams of active carbon, filtered and neutralized with aqueous ammonia. The separated crystals were filtered, washed with water and dried to give 72.0 grams (85% yield) of 4,4'-bis(3-aminophenoxy)biphenyl as colorless crystals having a melting point of 144°-146° C. The purity was 99.6% according to high-speed liquid chromatography.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O1CCCC1>[CH2:34]([NH:36][C:37]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH:21]=1)=[O:38])[CH3:35]
Reactant: Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Reactant: CCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
A mixture of [3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]amine hydrochloride (Example 212, 100 mg, 0.26 mmol) and triethylamine (0.05 mL, 0.36 mmol) in tetrahydrofuran (2 mL) was cooled to 0° C. and ethyl isocyanate (0.08 mL, 0.31 mmol) added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound as a white solid (27 mg, 24%). δH (500 MHz, d6 DMSO): 8.85 (1H, s), 8.15 (1H, s), 7.86 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz), 7.67 (2H, dd, J=5.7, 8.5 Hz), 7.50-7.48 (1H, m), 7.43-7.40 (3H, m), 7.27 (1H, d, J=16.5 Hz), 7.22 (2H, t, J=8.8 Hz), 6.20 (1H, t, J=5.4 Hz), 3.12-3.06 (2H, m), 1.03 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>CO>[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:4][CH:1]2[CH2:3][CH2:2]2)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC1CC1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(CNC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Cyclopropylamine (1.4 g, 24.4 mmol) and acetic acid (0.5 ml) were added to a solution of 4-formyl-piperidine-1-carboxylic acid benzyl ester from Example E33.2 (5.5 g, 22.2 mmol) in methanol (49.5 ml) and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (1.84 g, 28.9 mmol) was added and the mixture was stirred for 20 h at room temperature under an inert atmosphere. Solvents were removed in vacuo and azeotroped with toluene. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (3.0 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11](=[C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23]3)[S:10]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[CH2:14]([N:13]1[C:12](=[O:21])[C:11](=[C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2)[S:10][C:9]1=[N:8][C:4]1[CH:3]=[C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)O1
Reactant: CN1C(=C2SC(=Nc3cccc(N)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN1C(=C2SC(=Nc3cccc(NC(=O)CCC(=O)O)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a 25 mL flask was added 2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one (100 mg, 225 μmol), anhydrous DCM (5 mL) and CHCl3 (3 mL). To the solution was added succinic anhydride (23 mg, 239 μmol). The reaction solution was allowed to stir at 50° C. for 1.5 h. The white precipitates were collected by filtration under reduced pressure, washed with DCM (10 mL) and hexanes (20 mL), and then dried under vacuum to give the title compound (75 mg, 61%). MS(ESI): 545 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][N:12]=[C:13]3[C:17]=2[NH:16][CH:15]=[C:14]3[C:18](=[O:22])[C:19]([O-])=[O:20])=[CH:5][CH:4]=1.[K+].[C:24]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:24]([N:32]1[CH2:37][CH2:36][N:35]([C:19](=[O:20])[C:18]([C:14]2[C:13]3[C:17](=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:10]=[CH:11][N:12]=3)[NH:16][CH:15]=2)=[O:22])[CH2:34][CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2ccnc3c(C(=O)C(=O)[O-])c[nH]c23)cc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccnc3c(C(=O)C(=O)N4CCN(C(=O)c5ccccc5)CC4)c[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The procedure for the preparation of Examples 65-67 is the same as that described previously for the preparation of Precursor 5a and is as follows: Potassium 7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate, Precursor 4c (147 mg, 0.44 mmol), an appropriate 1-benzoylpiperazine derivative (0.44 mmol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (101 mg, 0.44 mol) and Hunig's Base (0.5 mL) were combined in 5 mL of DMF. The mixture was stirred at rt for 8 h. DMF was removed via evaporation at reduced pressure and the residue was purified using a Shimadzu automated preparative HPLC System to give the corresponding 1-benzoyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetyl]-piperazine derivative.