Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:17]=1.BrN1C(=O)CCC1=O.C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1nc2c(s1)CCc1cc(Cl)ccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from step (i) (6.05 g) in 1,2-dichloroethane (85 ml) with N-bromosuccinimide (4.1 g) was irradiated with a 500 Watt halogen lamp for 1 h. After cooling to room temperature, triethylamine (7 ml) was added with further stirring for 0.5 hours. The solvents were evaporated under reduced pressure and the residue triturated with acetone, filtered and then further washed with water and then dried under vacuum to leave the subtitle compound as a cream solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](O)=O)[CH2:12]1)=O)C1C=CC=CC=1.Cl[C:21]1[N:22]=[N:23][C:24]([NH:27][NH2:28])=[CH:25][CH:26]=1.Cl>C(Cl)Cl>[N:11]1([C:21]2[CH:26]=[CH:25][C:24]3[N:23]([C:17]([CH:13]4[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]4)=[N:28][N:27]=3)[N:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Solvent: ClCCl
Product: c1cc2nnc(C3CCCNC3)n2nc1N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of 1-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid (2.44 g), 3-chloro-6-hydrazinopyridazine (1.34 g), WSCD hydrochloride (2.13 g) and methylene chloride (60 ml) was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant reside was combined with acetic acid (80 ml), stirred at 100° C. for 2 days, and then the solvent was distilled off under reduced pressure. The resultant crude crystals were washed with ethanol, and stirred with heating under reflux in piperidine (10 ml) for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: chloroform:methanol=97:3). The resultant colorless solids were combined with ethanol (40 ml) and 10% palladium-carbon (150 mg), and stirred under hydrogen atmosphere at room temperature for 6 hours, and then the catalyst was filtered off. The resultant filtrate was concentrated under reduced pressure to obtain 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo[4,3-b]pyridazine (1.18 g) as a colorless amorphous.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[C:12]1([C:18]#[C:19][CH:20]2[CH:25]=[CH:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:22][CH:21]=[C:20]([C:19]#[C:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:25][CH2:24]2)=[CH:9][N:8]=1
Reactant: C(#CC1C=CNCC1)c1ccccc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CC=C(C#Cc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.19 g (0.00098 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 20 ml of dimethyl-formamide was treated with 0.15 g (0.82 mol) of 4-phenylethynyl-1,2,3,4-tetrahydro-pyridine and 0.34 ml (0.0024 mol) of triethylamine and the mixture was stirred at room temperature under argon for 16 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/ethanol 8:1 as the eluent and digested in diethyl ether. 0.10 g (34%) of 2-methyl-5-(4-phenylethynyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidin-4-ylamine as white crystals; m.p. 187°-188°.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH:48]=[CH2:49].Cl[C:57]1[N:62]=[CH:61][C:60]([O:63][S:64]([C:67]2[CH:72]=[CH:71][C:70]([CH:73]([CH3:75])[CH3:74])=[CH:69][CH:68]=2)(=[O:66])=[O:65])=[CH:59][CH:58]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:47]([N:50]1[CH2:55][CH2:54][N:53]([C:57]2[N:62]=[CH:61][C:60]([O:63][S:64]([C:67]3[CH:68]=[CH:69][C:70]([CH:73]([CH3:75])[CH3:74])=[CH:71][CH:72]=3)(=[O:66])=[O:65])=[CH:59][CH:58]=2)[CH2:52][CH2:51]1)[CH:48]=[CH2:49]
Reactant: C=CCN1CCNCC1
Reactant: CC(C)c1ccc(S(=O)(=O)Oc2ccc(Cl)nc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C=CCN1CCN(c2ccc(OS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 50 °C
Yield: 21 %

Procedure:
A flask containing 45 mg of palladium(II) acetate (0.2 mmol), 126 mg of BINAP (0.20 mmol) and 0.233 mg of sodium tert-butylate in dry toluene (15 mL) was flushed with nitrogen 1.275 g of 1-allylpiperazin (10 mmol) were added and the reaction mixture was heated to 50° C. 630 mg of 4-isopropyl-benzenesulfonic acid 6-chloro-pyridin-3-yl ester (2.0 mmol) were dissolved in toluene and the solution was slowly added over a period of 10 minutes into the reaction mixture with stirring. The mixture was heated to reflux with stirring for 7 h. Thereby 4-isopropyl-benzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester was obtained in 21% yield.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[C:9]([O:17][CH2:18][C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:28])[C:6]=2[C:5]([Cl:29])=[CH:4][CH:3]=1.[NH:30]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][OH:37])[NH2:31].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:29][C:5]1[CH:4]=[CH:3][C:2]2[N:30]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][OH:37])[N:31]=[C:14]3[C:13]4[C:8](=[C:9]([O:17][CH2:18][C:19]5[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=5[CH3:27])[CH:10]=[CH:11][CH:12]=4)[C:7](=[O:28])[C:6]=1[C:15]=23
Reactant: NNCCNCCO
Reactant: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc(Cl)c2C3=O)c(C)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCNCCO)c(C)c1

Procedure:
A mechanically stirred mixture of 310 g (0.73 mol) of 1,4-dichloro-5-[(2,4,6-trimethylphenyl)methoxy]-9,10-anthracenedione, 260 g (2.19 mol) of 2-[(2-hydrazinoethyl)amino]ethanol, 381 ml (2.19 mol) of N,N-diisopropylethylamine, and 4.8 l of acetonitrile was heated at reflux for 22 hr. The cooled mixture was concentrated in vacuo to leave a residue, showing a ~1:4 ratio of 12:13, that was triturated with water. The solids were collected by filtration, washed with methanol, and dried at 220 mm/50° C./18 hr to leave 237 g (66%) of crude 13, mp 147°-158° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
A solution of indole-5-carboxylic acid (68.3 g), benzyl alcohol (64.9 g) and triphenylphosphine (157.0 g) in tetrahydrofuran (1.2 L) was cooled to 5° C. and treated dropwise with diethyl azodicarboxylate (90.0 g). Upon completion of the addition, the mixture was allowed to warm to room temperature. The reaction was stirred for 24 hours and then evaporated. The residue was taken up in diethyl ether (1 L) and filtered. The filtrate was evaporated to give a yellow syrup which was purified by flash chromatography, eluting sequentially with 2:1, 1:1 and 1:2 hexane:methylene chloride, to afford a yellow-white solid. This material was triturated with 1:1 hexane: methylene chloride (300 mL) and filtered to give benzyl indole-5-carboxylate as a white solid (74.2 g, 70%); mp 127°-129 ° C.; partial NMR (300 MHz, CDCl3): 5.39 (s, 2H, CH2), 6.61 (m, 1H, indole-H(2)), 8.56 (br, 1H, NH).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[C:12]([CH3:20])([CH3:19])[CH2:13][S:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[C:1]1([C:7]2[NH:11][C:10]3[C:12]([CH3:20])([CH3:19])[CH2:13][S:14](=[O:22])[CH2:15][C:16]([CH3:18])([CH3:17])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)CSCC(C)(C)c2[nH]c(-c3ccccc3)nc21
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CS(=O)CC(C)(C)c2[nH]c(-c3ccccc3)nc21
Temperature: 2 °C

Procedure:
1.43 g of 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino[4,5-d]imidazole are dissolved in 75 ml of methanol and cooled to 2° C. with stirring. The solution is treated dropwise at this temperature with a solution of 1.3 g of sodium periodate in 28 ml of water. The mixture is left to react-out at the same temperature for 3 hours. Thereupon, 25 ml of methanol are added. After stirring for 5 hours at room temperature, the solution is concentrated. The product is left to crystallize-out while cooling with ice. The precipitate is removed by filtration and the crystals are covered with acetone and ether. After filtration, the 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino-[4,5-d]-imidazole 6-oxide is recrystallized from ethanol/n-hexane, m.p. 273°-275° C.; m.p. of the hydrochloride: 300° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Clc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
20.5 g (100 mmol) of 2-bromo-5-chlorotoluene was dissolved in 200 ml of carbon tetrachloride, 0.2 g (1 mmol) of AIBN and 19.6 g (110 mmol) of N-bromosuccinimide were added thereto, the resulting mixture was refluxed for 2 hours and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and with 50 ml of a brine solution, dried over anhydrous MgSO4, and distilled under a reduced pressure to obtain an oil containing a small amount of the starting material. The oil was dissolved in 20 ml of hexane, and recrystallized at room temperature to obtain 22.7 g (yield 80%) of 2-bromo-1-bromomethyl-5-chlorobenzene.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[CH:5][C:6](=[NH:17])[N:7]([CH:9]([CH3:16])[C:10](=O)[C:11]([O:13][CH3:14])=[O:12])[CH:8]=1>CO.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH3:16])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:17]=2)[CH:8]=1
Reactant: COC(=O)C(=O)C(C)n1cc(Cl)ccc1=N
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2ccc(Cl)cn2c1C
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of methyl 3-(5-chloro-2-iminopyridin-1(2H)-yl)-2-oxobutanoate hydrobromide (8.51 g, 26.3 mmol) in MeOH (50 mL) was heated to reflux for 16 h, cooled to room temperature, and concentrated to give a white solid. The solid was dissolved in a mixture of EtOAc and saturated NaHCO3, the aqueous phase was discarded and the organic phase was washed with saturated NaHCO3 (1×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated to give methyl 6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylate (5.68 g, 25.3 mmol, 96% yield) as an off white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.C(OCC)(=O)C>C1COCC1>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[S:9][C:8]2=[C:4]([S:3][C:2]([F:1])([F:12])[F:13])[N:5]=[CH:6][N:7]2[CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: FC(F)(F)Sc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC(F)(F)F)c2s1
Temperature: -65 °C

Procedure:
7-Trifluoromethylthioimidazo[5,1-b]thiazole (590 mg) was dissolved in 10 ml of THF under an argon atmosphere, and the solution was cooled to −65° C. Tri-n-butylstannyl chloride (2.07 ml) and 7.2 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added dropwise in that order to the cooled solution. The temperature of the mixture was raised to −40° C. over a period of 30 min. Ethyl acetate (40 ml) was added to the reaction solution, and the mixture was washed with 40 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, and was then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to prepare 951 mg of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]1[O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6]1>O>[N+:1]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][O:13][C:8]=2[CH:9]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)OCO2
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 0 °C

Procedure:
To 150 mls. of concentrated nitric acid cooled to and maintained at 0°C. is added 100 gms. of methylenedioxybenzene dropwise with vigorous stirring. At the end of the addition, the reaction mixture is diluted with several volumes of water, the precipitated solids collected by vacuum filtration and washed with several portions of water. Recrystallization of the crude solids from methanol provided 1-nitro-3,4-methylenedioxybenzene, m.p. 130°-141°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:31])[C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (160 g, 0.369 mol), potassium carbonate (76.6 g, 0.554 mol) and iodomethane (34.5 mL, 0.554 mol) in N,N-dimethylformamide is stirred at room temperature for 4 hours, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extract is diluted with hexanes, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange foam (163 g, 98.8%) which is identified by NMR spectral analyses.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=C(CC)C(O)=CC=3OCCC)OC(=O)CC(=O)C2)CCCC1.CO[CH:59]([C:61]1[N:69]=[C:64]2[N:65]=[CH:66][CH:67]=[CH:68][N:63]2[N:62]=1)O.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:59][C:61]3[N:69]=[C:64]4[N:65]=[CH:66][CH:67]=[CH:68][N:63]4[N:62]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1-c1ncco1
Reactant: COC(O)c1nc2ncccn2n1
Agent: CCCOc1cc(O)c(CC)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncccn4n3)C(=O)O2)ccc1-c1ncco1

Procedure:
The title compound was prepared analogously to Example A(1) where 6-cyclopentyl-6-{2-[3-ethyl-4-(1,3-oxazol-2-yl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (Example A(135)) was substituted in place of 6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-propoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione in that example and methoxy-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl-methanol was substituted in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield (57 mg, 11%). 1H NMR (300 MHz, CDCl3): δ ppm 1.20 (t, J=7.44 Hz, 3 H) 1.53–1.67 (m, 8 H) 2.00–2.11 (m, 2 H) 2.35–2.47 (m, 1 H) 2.51–2.63 (m, 1 H) 2.65–2.72 (m, 2 H) 2.72–2.83 (m, 2 H) 3.04 (q, J=7.54 Hz, 2 H) 4.14 (d, J=3.77 Hz, 2 H) 7.04–7.10 (m, 2 H) 7.14–7.20 (m, 1 H) 7.25 (s, 1 H) 7.71 (s, 1 H) 7.82 (d, J=7.91 Hz, 1 H) 8.84 (d, J=5.46 Hz, 2 H). MS (ESI): 514 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[N+:14]([O-])([O:16]C(=O)C)=[O:15].[N+]([O-])(O)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(Cl)n(-c2ccccc2)n1
Reactant: CC(=O)O[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: Cc1nn(-c2ccccc2)c(Cl)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 9.6 g (0.05 mole) of 5-chloro-3-methyl-1-phenylpyrazole and 25 ml of acetic anhydride was added at 10°C to a solution of acetyl nitrate prepared from 25 ml of 90% nitric acid and 10 ml of acetic anhydride. The solution was stirred 2 hours at 20°-30°C and carefully poured onto ice water. The solid was filtered off and washed with cold water. One recrystallization from ethanol gave long white needles of product.
Reaction SMILES: Br[C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[Cu](C#N)[C:15]#[N:16]>CN1CCCC1=O.CCOC(C)=O.Cl>[C:10]([C:4]1[C:3]([OH:13])=[C:2]([C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[C:15]#[N:16])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1O
Temperature: 200 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (4.85 g, 18.4 mmol) and copper cyanide (2.47 g, 27.6 mmol) in N-methylpyrrolidinone (15 mL) was heated at 200° C. for 1 h. After cooled to rt, the mixture was diluted with EtOAc and 1 N HCl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, then brine and dried over magnesium sulfate, then concentrated to dry under reduced pressure. The residue was used directly in next step (3.7 g, 96%). LCMS calculated for C10H9ClNO2 (M+H)+: m/z=210.0; Found: 210.1.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[N+:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[C:22]([CH:6]([C:5]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:4]=2[O:3][CH3:2])[N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:21]=1
Reactant: COc1cccc(C=[N+]2CCOCC2)c1OC
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: [Cl-]
Product: COc1cccc(C(c2cc(Cl)c3ccccc3c2O)N2CCOCC2)c1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-(2,3-dimethoxy-benzylidene)-morpholin-4-ium chloride and 4-chloro-1-naphthol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[O:15])=[CH:10][CH:9]=3)[C:5]([CH3:21])=[CH:4][CH:3]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
4-Chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)benzamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 4-chlorobenzoic acid using method B. LCMS: retention time 3.73 min, MH+419.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32]([NH:15][C@@H:5]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared as in EXAMPLE 1, substituting 2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride (prepared as in Example 2, Part A) and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid in Part C. HPLC: RT=10.48 min. MS (ESI−): mass calcd. for C22H14Cl4N4O5S2, 620.31; m/z found, 617/619/621 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.64 (s, 1H), 8.53 (s, 2H), 8.46 (d, J=7.0, 1H), 8.29 (d, J=8.7, 1H), 7.89 (dd, J=8.8, 7.1, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.56 (d, J=1.8, 1H), 7.49 (d, J=8.2, 1H), 7.34 (dd, J=8.2, 1.8, 1H), 5.00-4.94 (m, 1H), 3.40-3.36 (m, 1H), 3.25-3.17 (m, 1H).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH:19]([OH:22])CO)=[CH:15][C:14]([O:23][CH3:24])=[CH:13][CH:12]=2>O.CC(C)=O>[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH:19]=[O:22])=[CH:15][C:14]([O:23][CH3:24])=[CH:13][CH:12]=2
Reactant: COc1ccc2ncc(Cl)c(CC(O)CO)c2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2ncc(Cl)c(CC=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of sodium periodate (2.88 g, 13.5 mmol, 1.2 eq) in water (30 mL) is added dropwise at 0° C. to a stirred solution of 3-(3-chloro-6-methoxy-quinolin-4-yl)-propane-1,2-diol (3.0 g, 11.2 mmol, 1.0 eq) in acetone (50 mL) and water (20 mL). After 30 minutes stirring at 0° C. the reaction mixture is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to afford (3-chloro-6-methoxy-quinolin-4-yl)-acetaldehyde as a light brown solid (2.6 g, 99% yield).