Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[N:5]([CH2:12][CH2:13][N:14]=3)[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.O>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]2[C:4]3[N:5]([CH:12]=[CH:13][N:14]=3)[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Brc1cccc2c1C1=NCCN1C=N2
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: O
Product: Brc1cccc2ncn3ccnc3c12
Yield: 53.6 %

Procedure:
4. 242 g of manganese dioxide are added to a warm solution of 22 g of 10-bromo-2,3-dihydroimidazo[1,2-c]quinazoline in 2 l of benzene in a reaction vessel which is provided with a water separator. The mixture is heated at reflux temperature for 15 h. Then, a further 8 g of maganese dioxide are added thereto and the mixture is heated at reflux temperature for a further 1 h. The hot reaction mixture is filtered over Dicalite. The filter cake is rinsed with 1 l of hot benzene, then again boiled up in 1.5 l of dichloromethane/ethanol 199:1 and again filtered. The filtered solutions are concentrated to about 1.51 in a vacuum. A byproduct crystallizes and is filtered off (1.65 g). The filtrate is chromatographed over a column of 2 kg of silica gel. A total of 12.0 g of the desired product is eluted with dichloromethane/ethanol 99:1. 11.7 g of 10-bromoimidazo[1,2-c]quinazoline of m.p. 215°-216° C. are obtained after crystallization from ethyl acetate.
Reaction SMILES: [Li]C(CC)C.BrC1C=CC(F)=CN=1.C[Si](C)(C)C#CC(=O)C.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:44])([C:38]#[C:39][Si](C)(C)C)[CH3:37])=[N:34][CH:35]=1>C(OCC)C.CO>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:44])([C:38]#[CH:39])[CH3:37])=[N:34][CH:35]=1
Reactant: CC(O)(C#C[Si](C)(C)C)c1ccc(F)cn1
Agent: CC(=O)C#C[Si](C)(C)C
Agent: Fc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOCC
Product: C#CC(C)(O)c1ccc(F)cn1
Reaction time: 1 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure C. In a 100-mL 3-necked round-bottom flask, s-BuLi (1.3M in hexane 10 mL) was added dropwise into a solution of 2-bromo-5-fluoropyridine (1.76 g, 10.00 mmol, 1.00 equiv) in ethyl ether (20 mL) under −76° C. The resulting solution was stirred for 1 h, then 4-(trimethylsilyl)but-3-yn-2-one (1.54 g, 10.98 mmol, 1.10 equiv) was added. The resulting solution was stirred for 2 h at −76° C. The reaction was then quenched by the addition of 10 mL of NH4Cl (sat., aq.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.2 g (crude) of 2-(5-fluoropyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol as brown oil. In a 50-mL round-bottom flask, potassium carbonate (2.8 g, 20.29 mmol, 2.19 equiv) was added batchwise into a solution of 2-(5-fluoropyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol (2.2 g, 9.27 mmol, 1.00 equiv) in methanol (25 mL). The resulting solution was stirred for 2 h at room temperature. When completed monitored by TLC and LCMS, solvent was concentrated under vacuum. The residue was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of brine. The solids were filtered out. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 700 mg (46%) of 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol as a light brown solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:25]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:31]4[CH2:32][CH2:33][N:28]([CH:25]5[CH2:27][CH2:26]5)[CH2:29][CH2:30]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Reactant: C1CN(C2CC2)CCN1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from rac-(1S,35)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and 1-cyclopropyl-piperazine to afford the desired product as an off-white solid. MS (EI): 477.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CC(C)O
Product: CC(O)c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a round-bottomed flask provided with magnetic stirrer and reflux condenser or in a 100 ml autoclave, 5.0 g (32.3 mmol) of p-chloroacetophenone, 45 g of isopropyl alcohol and 1.0 g of catalyst were heated under reflux or at 120° C. After the end of the reaction time, the reaction mixture was analyzed by gas chromatography and the yield was determined. The results are summarized in Table 3 below:
Reaction SMILES: [CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:17][CH2:18][OH:19])[C:11]([CH3:21])([CH3:20])[CH2:10]1)C(=O)C)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>Cl>[CH2:1]([NH:5][CH:9]1[CH2:10][C:11]([CH3:20])([CH3:21])[N:12]([CH2:17][CH2:18][OH:19])[C:13]([CH3:15])([CH3:16])[CH2:14]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(C)=O)C1CC(C)(C)N(CCO)C(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCNC1CC(C)(C)N(CCO)C(C)(C)C1
Yield: 74.9 %

Procedure:
) A solution of 12.6 g (42.2 mmol) of N-n-butyl-N-[ 1-(2-hydroxyethyl)-2,2,6,6-tetramethylpiperidin-4-yl]acetamide [Example 1bη2] in 180 ml of 2N hydrochloric acid is refluxed for 48 hours. The reaction mixture is then cooled 0°-5 C. and, after addition of 40 ml of 30% sodium hydroxide solution, extracted twice with toluene. The organic phases are washed with water, combined, dried over sodium sulfate, and concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system ethyl acetate/ethanol/triethylamine=50:2:1 yields 8.1 g (68%) of 2-(4-n-butylamino-2,2,6,6-tetramethylpiperidin-1-yl) ethanol (208) as a white powder of m.p. 106°-111° C. Analysis: calcd: C 70.26%; H 12.58%; N 10.92%. found: C 70.42%; H 12.85%; N 11.00%. ##STR65## τ) 833 g (5.30 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 418 g (1.05 mol) of 2-butyne-1,4-diol-ditosylate [C.A. Registry No. 6337-59-3] in 3.6 1 of acetonitrile are placed, under argon, in a round-bottomed flask equipped with magnetic stirrer and condenser. The reaction mixture is refluxed overnight, then cooled, poured on ice and extracted repeatedly with ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 295 g (76%) of 1,4-bis(4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)-but-2-yne (209), m.p. 203.4° C., in the form of white crystals. Analysis: calcd: C 72.48%; H 11.06%; N 7.68%. found: C 72.52%; H 11.12%; N 7.75%. ##STR66## κ) The HALS diol (210) is known and described in U.S. Pat. No. 4,569,997 (Ciba-Geigy, Example 1, column 14). ##STR67## λ)1.) 9.15 g (50 mmol) of adipyl dichloride are added dropwise at 0°-5° C., under nitrogen, to a stirred solution of 22.2 g (105 mmol) of 4-n-butylamino-2,2,6,6-tetramethylpiperidine IEP-A-302 020, Example 1, page 41 in 70 ml of triethylamine and 150 ml of toluene. After c. 30 minutes the reaction mixture is heated to c. 100° C. and stirred for 90 minutes at this temperature. The resultant dense suspension is thereafter cooled to room temperature, filtered to remove the salts, and the filtrate is concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system ethyl acetate/ethanol/triethylamine=20:1:1 and crystallisation of the pure fractions from hexane yields 17.15 g (64%) of N,N'-di-n-butyl-N,N'-bis-(2,2,6,6-tetramethyl-4-piperidinyl)hexane diamide as a white powder; m.p. 134°-144° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.ClC(OCC)=O>CC(C)=O>[Cl:1][CH2:2][C:3]1[O:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[N:5]=1
Reactant: CC(C)(NC(=O)CCl)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Product: CC1(C)N=C(CCl)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a stirring mixture of 2-(2-chloro-acetylamino)-2-methyl propionic acid (18.0 g; 0.100 mol), trichylamine (11.1 g; 0.110 mol) and 100 ml of acetone in a round bottom flask, cooled with an ice bath, was added ethyl chloroformate (10.5 ml; 0.110 mol) over a period of 10 minutes. The reaction mixture was then allowed to warm to room temperature and was stirred for 2 hours. The mixture was then filtered, and the filtrate was concentrated under vacuum. Hexane (200 ml) was added to the residue, and the mixture was filtered. After removal of the solvent under vacuum, the filtrate residue was distilled under reduced pressure (59-60°; 7 mmHg) to give 13.2 g (82%) of a colorless oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([O:19]C)=[O:18])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].CO.Cl>O>[CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 84.7 %

Procedure:
A mixture of methyl 3-(butylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.460 g, 1.58 mmol), sodium methoxide (0.257 g, 4.75 mmol), methanol (6.4 mL) and water (1.6 mL) was refluxed overnight. The mixture was cooled in an ice-bath and conc. HCl (0.390 mL, 4.75 mmol) was added. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.370 g, 85%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[C:19]([F:30])=[CH:20][C:21]([F:29])=[C:22]([CH:28]=1)[C:23]([NH:25][O:26][CH3:27])=[O:24].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:29][C:21]1[CH:20]=[C:19]([F:30])[C:18]([NH:17][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:28][C:22]=1[C:23]([NH:25][O:26][CH3:27])=[O:24]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: CONC(=O)c1cc(N)c(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CONC(=O)c1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 2.9 %

Procedure:
Compound 83 (100 mg, 0.43 mmol), 5-amino-2,4-difluoro-N-methoxy-benzamide (124 mg, 0.52 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (21 mg, 0.04 mmol), and NaOtBu (125 mg, 1.30 mmol) were suspended in dioxane (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAc/H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM to provide 158 (5 mg, 3% yield) as a white solid. LC-MS (M+H=397, obsd.=397).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[C:2]1([C:1]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Product: c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 190 °C

Procedure:
An autoclave is charged with 2.43 g. o-nitrophenyl benzoate, 0.50 g. 5% palladium-on-carbon, 0.25 g. ferric chloride and 20 ml. of acetonitrile, purged with nitrogen, pressurized to 5,000 psig. with carbon monoxide, and heated at 190° C. for 6 hours. Analysis of the reaction mixture by vapor phase chromatography shows that the major component (87%) is 2-phenylbenzoxazole and a minor component is 3-benzoyl-2-benzoxazolinone. The catalyst is removed and the solvent is evaporated. Chromatography of the residual oil on alumina yields 2-phenylbenzoxazole, melting point 100°-102° C., identical with an authentic sample by mixed melting point and infrared spectrum.
Reaction SMILES: C[O:2][C:3]([CH:5]([N:13]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15](OCC2C=CC=CC=2)[C:14]1=[O:31])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C[OH:33]>[Pd]>[OH:33][C@@:5]([C:3]([OH:2])=[O:4])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:13][C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO
Reactant: COC(=O)C(Cc1ccccc1)N1C(=O)C(OCc2ccccc2)C1c1ccccc1
Agent: [Pd]
Product: O=C(CCc1ccccc1)N[C@@](O)(Cc1ccccc1)C(=O)O
Reaction time: 48 h
Yield: 100 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonyl-2-phenylethyl)-3-benzyloxy-4-phenylazetidin-2-one (1.0 g.) was subjected to hydrogenolysis at 50° C. in methanol (50 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (255 mg.). The reaction was completed in 48 hours. The same after-treatment as in Example 1 was followed to give methyl ester of α-hydroxy-β-phenylpropionylphenylalanine (784 mg., yield: 100%), which was an oil.
Reaction SMILES: Cl.O1CCOCC1.[K].C(OC(=O)[NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][C:28](=[O:30])[NH:27][S:26]2(=[O:32])=[O:31])=[C:21]([OH:33])[CH:20]=1)(C)(C)C>>[NH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[S:26](=[O:32])(=[O:31])[NH:27][C:28](=[O:30])[CH2:29]2)=[C:21]([OH:33])[CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Agent: Cl
Agent: [K]
Solvent: C1COCCO1
Product: NCCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To HCl/dioxane (5 mL, 4.0 M) is added {3-[3-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propyl}-carbamic acid tert-butyl ester potassium salt (0.7 g, 1.65 mmol) and the mixture is stirred at RT for 4 h. The solvent is removed under reduced pressure and water is added. The solution is washed with ether and the aqueous phase lyophilized to give the hydrochloride salt of the title compound as a yellow powder: (M−1)−=284. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.77-1.88 (m, 2 H) 2.58 (t, J=7.71 Hz, 2 H) 2.72-2.81 (m, 2 H) 4.40 (s, 2 H) 6.68 (d, J=8.34 Hz, 1 H) 6.81 (s, 1 H) 7.26 (d, J=8.08 Hz, 1 H)
Reaction SMILES: [Br-].[CH:2](=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5].C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[C:19]1([CH2:6][CH2:4][CH2:3][CH2:9][CH2:8][CH2:7][O:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[CH:2]=[O:10])[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1O
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCCCCc1ccccc1
Temperature: 100 °C

Procedure:
A solution of 6-phenylhexanoic acid (19.8 mmoles) in sieve dried tetrahydrofuran (5 ml) and reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 6-phenylhexanol. To an ice cold solution of the hexanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphospine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 6-phenylhexyl bromide as an oil. A mixture of the bromide (8.00 mmoles), salicylaldehyde (8.19 mmoles) and potassium carbonate (9.33 mmoles) in dimethylformamide (10 ml) was heated to 100° C. and maintained at that temperature for one hour. The cooled reaction mixture was taken up in hexane (50 ml) and washed with 5% sodium hydroxide (50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation yielded a colorless oil which was purified by flash chromatography over silica gel with 5% ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)c(C)c4)CC3)nn2C(C)(C)C)cc1

Procedure:
118 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(3,4-dimethylphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: N1(C(Cl)=O)CCCC1.[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:17]([NH:16][C:14]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:15])=[S:18])=[CH:39][CH:40]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)N1CCCC1
Agent: O=C(N=C=S)N1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
1-Pyrrolidinecarbonyl isothiocyanate was prepared using commercially available 1-pyrrolidinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Pyrrolidinecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (48 mg, yield 63%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.[Cl:35][C:36]1[S:40][C:39]([S:41](/[N:44]=[C:45]2\[CH:46]=[C:47](Cl)[C:48](=[O:55])[C:49]3[C:54]\2=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:43])=[O:42])=[CH:38][CH:37]=1>>[Cl:35][C:36]1[S:40][C:39]([S:41](/[N:44]=[C:45]2\[CH:46]=[C:47]([S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[C:48](=[O:55])[C:49]3[C:54]\2=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:43])=[O:42])=[CH:38][CH:37]=1.[CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:21])=[O:22])/[CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)s2)c2ccccc21
Agent: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(Cl)s2)c2ccccc2C1=O

Procedure:
(E)-5-chloro-N-(3-(1-methyl-1H-tetrazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13aa) was prepared according to the procedure for 13x except using 12d, affording 77.1 mg (85.3%) title compound as a yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][N:15]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: NCCO
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCO

Procedure:
Phthalic anhydride (100 g, 0.67M) was condensed with monoethanol amine (41.2 g, 0.91 M) at 160-178° C. for 4 hours. The reaction mass was quenched in hot water at 95° C., cooled and filtered and washed with water twice and dried at 90-95° C. for 12 hours. Yield 118 g.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Cl:9][C:10]1[C:15](Cl)=[N:14][CH:13]=[CH:12][N:11]=1>CN(C)C=O>[Cl:9][C:10]1[C:15]([N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C1CCCN1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
Sodium hydride (60% in mineral oil, 67 mg, 1.62 mmol) was added to a solution of pyrrolidinone (0.12 ml, 1.54 mmol) in dry dimethylformamide (5 ml) under argon at 0° C. The mixture was allowed to warm to room temperature over 1.5 hours. A solution of 2,3-dichloropyrazine (D46, Step 2) (250 mg, 1.69 mmol) in dry dimethylformamide (2 ml) was added and the mixture stirred at room temperature under argon for 2 hours. The mixture was poured onto water (30 ml) and was extracted with ethyl acetate (×3). The ethyl acetate extracts were combined, washed with brine, dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:1) to afford the title compound (0.10 g); MS (ES+) m/e 198 [M+H]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]([C:10]1C=[CH:17][CH:16]=[CH:15][C:11]=1C(O)=O)[CH3:9]>C(Cl)Cl>[CH3:7][N:8]([C:10]1[CH:11]=[CH:15][CH:16]=[CH:17][C:1]=1[C:2]([Cl:4])=[O:3])[CH3:9]
Reactant: CN(C)c1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)c1ccccc1C(=O)Cl
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (371 g) was added to a suspension prepared by adding 3.6 L of dry methylene chloride to 358 g of N,N-dimethylaminobenzoic acid. A vessel containing the resultant solution was dipped in an oil bath, and the solution was stirred for 2.5 hr while controlling the internal temperature at about 40° C. The solvent was removed by evaporation under the reduced pressure, and the residue was vacuum dried to give a crude product of N,N-dimethylaminobenzoic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([N+:12]([O-])=O)[CH:4]=1.[CH:15]1([NH:18][C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)=[O:20])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][C:19](=[O:20])[C:21]2[CH:28]=[CH:27][C:24]([C:25]3[NH:12][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=4[N:9]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:17]1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Reactant: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COc1ccc2nc(-c3ccc(C(=O)NC4CC4)cc3)[nH]c2c1

Procedure:
Compound 635 was prepared according to the procedure similar to that described in Scheme III from 1-methoxy-3,4-dinitrobenzene and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C18H17N3O2: 308.14; found: 308.16.