Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A mixture of 20.8 g of 4-bromonitrobenzene and 17.2 g of 2-methoxyphenyl boronic acid in 340 mL of ethylene glycol dimethyl ether and 170 mL of 2 M sodium carbonate solution was purged with argon gas and then 3.6 g of Pd(PPh3)2Cl2 was added under argon atmosphere. The reaction mixture was heated in a sealed flask at 120° C. overnight. The reaction mixture was cooled down to room temperature. The mixture was filtered through diatomaceous earth and the filtrate was diluted with water and the product was extracted three times with EtOAc. The organic layers were combined, dried over magnesium sulfate (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield 17.1 g of 2-methoxy-4′-nitrobiphenyl as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of 3-bromo-5-nitrobenzoic acid (15.4 g, 62.6 mmol) in methanol (120 mL) and sulfuric acid (1.7 mL, 31 mmol) was heated to reflux overnight. After cooling to 0° C. for 0.5 h, the precipitated solid was filtered to give the desired product as a white solid (15.5 g, 95%). LCMS for C8H7BrNO4 (M+H)+: m/z=260.0, 262.0.
Reaction SMILES: [NH:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C(O)C.N1CCCCC1>[C:15]([C:14]([C:13]#[N:17])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)#[N:16]
Reactant: N#CCC#N
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1ccc(C=C(C#N)C#N)cc1

Procedure:
32.6 g (0.2 mol) of 4-acetaminobenzaldehyde and 13.74 g (0.208 mol) of malononitrile are initially charged in 140 ml of ethanol, and 24 drops of piperidine are added. The mixture is stirred at reflux for 30 min. After cooling, the crystals are filtered off with suction and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[N+:14]([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(=O)OCCc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)OCCc1ccc(N)c(N)c1
Reaction time: 2 h

Procedure:
Aryl nitrate 187 was dissolved in neat ethanol (25 mL) and 10% Pd/C (50 mg) was added, followed by 3 drops of glacial acetic acid. H2 gas was applied at 46 psi for 2 h with vigorous shaking, after which time TLC analysis indicated complete consumption of 187. The reaction mixture was filtered through a pad of Celite to remove the catalyst and the filtrate was concentrated under reduced pressure to give 188 as an oil. Column chromatography was employed with 10% MeOH/CH2Cl2 as eluant to give pure 188 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15].[BH4-].[Na+].[ClH:19]>CN(C)C=O.O>[ClH:19].[ClH:19].[NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: CCCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC1CCc2nc(N)sc2C1
Temperature: 50 °C

Procedure:
To a solution of 3.4 g (0.02 Mol) of 2,6-diamino- 4,5,6,7-tetrahydro-benzthiazole in 34 ml of dimethylformamide are added 1.8 g (0.022 Mol) of n- butanal and the mixture is heated to 50° C. for 1 hour. After cooling, the reaction solution is mixed with 0.8 g (0.02 Mol) of sodium borohydride and heated to 50° C. for 30 minutes. The solvent is largely eliminated in vacuo. Whilst cooling with ice, the residue is mixed with 20 ml of water and 2N hydrochloric acid until a pH of 1 is obtained. The aqueous solution is extracted with ethylacetate and the organic phase discarded. The aqueous phase is mixed with potassium carbonate until an alkaline reaction is obtained and then extracted with ethyl acetate. The organic phase is dried and concentrated. The compound crystallizes out when ethereal hydrochloric acid is added.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][NH2:23]>CO>[CH3:22][NH:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Solvent: CO
Product: CNCc1ccc(-c2nc3cccc(C(=O)OC)c3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To the solution of methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (500 mg, 1.4 mmol in methanol (10 mL), was added methylamine solution (4 mL), and the resulting mixture was stirred at room temperature for 1 hr, then heated to 30° C. for 30 min. Then the solvent was evaporated and purified by pre-HPLC to obtain methyl 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (as TFA salt, 90 mg, yield 42%). LC-MS (ESI) m/z 297 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:39](Br)([CH3:41])[CH3:40]>COCCOCCOC>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH:39]([CH3:41])[CH3:40])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:7])[CH3:3])=[CH:25][C:24]=2[OH:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:5]([CH3:6])[CH3:4])=[CH:17][C:16]=2[OH:22])[N:14]=1
Reactant: Oc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(OC(C)C)cc3O)nc(-c3ccc(OC(C)C)cc3O)n2)c(O)c1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
A mixture of 50.0 g (0.123 mol ) of 2,4,6-tris(2′,4′-dihydroxyphenyl)-1,3,5-triazine, 54.6 g (0.395 mol) of potassium carbonate, 1.0 g (0.006 mol) of potassium iodide (Merck, 99.0%) and 50.1 g (0.407 mol) of isopropyl bromide (Fluka, 99.0%) in 200 ml of diethylene glycol dimethyl ether (Diglyme, Merck, >99%) is held with stirring at 140° C. under a pressure of 3.8 bar for 24 h.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:26]([OH:27])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:26]1[C:17]([OH:16])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccccc2nc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3O)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (106 mg), 2,3-dihydroxyquinoline (50 mg), and 4-dimethylaminopyridine (124 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 150° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give 6,7-dimethoxy-4-(2-hydroxy-quinolin-3-yloxy)-quinoline (40 mg, yield 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:56][CH2:57][C:58]1[CH:69]=[CH:68][C:61]2[B:62]([OH:67])[O:63][C:64]([CH3:66])([CH3:65])[C:60]=2[CH:59]=1.Cl>CC#N>[OH:67][B:62]1[C:61]2[CH:68]=[CH:69][C:58]([CH2:57][NH:56][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])=[CH:59][C:60]=2[C:64]([CH3:66])([CH3:65])[O:63]1
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC1(C)OB(O)c2ccc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.665 mmol) and HATU (505.4 mg, 1.33 mmol) in CH3CN (15 mL) at rt can be stirred for 5 min. The mixture can be added to a solution of 5-(aminomethyl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (181.1 mg, 0.798 mmol) and TEA (268.7 mg, 2.66 mmol) in CH3CN (15 mL). Then the mixture can be stirred at rt for 2 h. The solution can be acidified with HCl (1 N) and extracted with EA. The combined organic layers can be washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue can be purified by prep-TLC to give the final title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:9]2[N:16]=[CH:17][N:18]=[C:8]2[NH:7][C:6]=1[CH3:19])=[O:4].[Br:20]Br.O>C(O)(=O)C>[Br:20][CH2:19][C:6]1[NH:7][C:8]2[N:9]([N:16]=[CH:17][N:18]=2)[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1=C(C)Nc2ncnn2C1c1cccs1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1=C(CBr)Nc2ncnn2C1c1cccs1
Yield: 50.6 %

Procedure:
In 300 ml of acetic acid is dissolved 29.5 g of 6-methoxycarbonyl-5-methyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine at 60° C. To the solution is added dropwise a solution of 16 g of bromine in 50 ml of acetic acid for 20 minutes with stirring. After stirring at room temperature for an hour, the reaction mixture is poured into water, extracted with chloroform, washed with water and potassium carbonate solution, dried and the solvent is evaporated under reduced pressure. The obtained pale yellow crystals are recrystallized from ethanol to give 18 g of 5-bromomethyl-6-methoxycarbonyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 155° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:13][CH2:14]2)[S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=555.3 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 4-chloro-aniline, and yielded (+/−)-trans-2-[4-(4-chloro-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(4-chloro-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(4-chloro-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].NC[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:10][CH2:9][CH2:8][NH:7][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:3][C:1]#[N:2]
Reactant: CSC(=NCCSCc1ccccn1)NC#N
Reactant: NCCc1ccccn1
Product: N#CN=C(NCCSCc1ccccn1)NCCSCc1ccccn1

Procedure:
The reaction of N-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea with 2-((2-aminoethyl)pyridine by the method described in Example 7 afforded the title compound m.p. 78°-80°.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[C:22]1([S:28]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n(S(=O)(=O)c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 7 h
Yield: 54.6 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil and 1.38 g (0.01 mole) of anhydrous potassium carbonate were suspended in 70 ml. of dioxane. 3.5 g (0.02 mole) of benzenesulfonyl chloride in 10 ml. of dioxane was dropwise added thereto and stirred at 80°C. for 7 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in a small amount of ethanol and allowed to stand at 5°C. overnight. There was obtained 2.95 g (54.6% yield) of 1-benzenesulfonyl-5-fluorouracil. The product was recrystallized from dioxane-ethanol and gave granular crystals melting at 256°-257°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Yield: 92 %

Procedure:
Thionyl chloride (11.1 mL, 15.3 mmol) was added to 4-acetoxybenzoic acid (2.50 g, 13.9 mmol), and the reaction was warmed to reflux. The reaction was cooled after heating for 3.5 hours, and concentrated in vacuo to give a colorless oil. Toluene was added to the residue and the mixture was concentrated in vacuo to remove any residual thionyl chloride. This process was repeated twice more to give 510 (2.54 g, 92%) as a colorless oil. This material was used in the next step without additional purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:36]>C(O)C>[Na+:36].[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=[C:8]2[S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O-:34])=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1

Procedure:
12 g of 8-(1.4.5-triphenylimidazol-2-yl mercapto)-octanoic acid are dissolved in 250 cc. of 96% ethanol. The equivalent amount of ethanolic sodalye (1 g of NaOH in 10 cc. of ethanol) is added and the mixture is stirred for a short time and evaporated to dryness in a vacuo. The residue is pulverized.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:17]2[CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: NC1CC1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1OC(F)(F)F
Yield: 67.4 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and cyclopropylamine (0.17 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.25 g, 68%) was provided after purification. MS (ESI) m/z 360. HPLC purity 100.0% at 210-370 nm, 9.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH2:39][C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Yield: 49.7 %

Procedure:
Method E. Reaction of oxalyl chloride (61 λL, 0.70 mmol) and benzoic acid 29 (204 mg, 0.47 mmol) with subsequent couping to 3-pyridinylmethylamine (53 λL, 0.52 mmol) gave benzamide 30 (123 mg, 50%) as a white powder: mp (EtOAc) 224-227° C.; 1H NMR δ 9.20 (t, J=5.9Hz, 1 H, CONH), 8.57 (d, J=1.7Hz, 1 H, H-2′), 8.47 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 8.00 (d, J=8.6Hz, 2 H, H-2, H-6), 7.88 (d, J=8.6Hz, 2H, H-3, H-5), 7.85 (ddd, J=8.6, 2.3, 1.9Hz, 2 H, H-2″, H-6″), 7.70-7.76 (m, 3H, H-4′, H-3″, H-5″), 7.36 (ddd, J=7.8, 4.7, 0.6Hz, 1 H, H-5′), 4.73 (s, 2 H, CH2SO2), 4.51 (d, J=5.9Hz, 2 H, CH2N), 2.22 (s, 3 H, CH3); 13C NMR δ 165.5, 158.1, 150.0, 148.9, 148.1, 137.8, 135.5, 135.2, 134.9, 132.3 (2), 130.4 (2), 128.8, 128.2, 128.1 (2), 125.7, 125.4 (2), 123.5, 52.8, 40.5, 9.7; MS m/z 526.1 (MH+, 100%), 528.1 (MH+, 100%). Anal. calcd for C24H20BrN3O4S.½H2O: C, 52.95; H, 4.07; N, 7.72. Found: C, 52.74; H, 3.67; N, 7.60%.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([Cl:13])[C:10]=2[Cl:12])[CH2:5][C:4]1([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH3:19].C(=O)([O-])O.[Na+:29]>O>[OH:1][N:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]([O-:18])=[O:17])=[C:9]([Cl:13])[C:10]=2[Cl:12])[CH2:5][C:4]1([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH3:19].[Na+:29]
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)[O-])c(Cl)c(Cl)c2C1=NO

Procedure:
100 Mg. of (1-hydroxyimino-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid are dissolved in 3 ml. of 0.1 N-sodium hydrogen carbonate solution. The solution is made up to 10 ml. with water and sterilized.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:31])[C:8]2[CH:13]=[N:12][C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[N:10][C:9]=2[N:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=1)=[O:5])C.[NH3:32]>CO>[CH:25]1([N:23]2[C:9]3[N:10]=[C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[N:12]=[CH:13][C:8]=3[C:7](=[O:31])[C:6]([C:4]([NH2:32])=[O:5])=[CH:24]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Reactant: N
Solvent: CO
Product: NC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
8-Cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (4.5 mg, 0.011 mmol) was added to 1.0 mL of 7 N ammonia in methanol. The mixture was stirred in a sealed tube at room temperature overnight. The solvent was evaporated to leave a white solid of 8-cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (4.0 mg, 95%). 1H NMR (400 MHz, CDCl3/CD3OD (20:1 v/v)) δ (ppm): 9.18 (s), 8.74 (s), 7.15 (br, 1H), 7.02 (br, 1H), 6.92 (br, 1H), 5.02 (m, 1H), 4.06 (t, J=6.6 Hz, 2H), 3.43 (br, 2H), 2.17 (m, 2H), 2.00-1.30 (br, 10H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C20H25N7O2: 396.21 (M+H). Found: 396.2.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])[N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[CH:6]=[CH:7][CH:8]=[C:9]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])[N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(Cl)nn12
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nn12

Procedure:
7-[5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.46 g, 1.4 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.557 g, 2.12 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.33 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (brs, 1H), 7.80-7.77 (m, 1H), 7.55-7.49 (m, 2H), 7.20-7.15 (m, 1H), 7.05-7.00 (m, 1H), 7.00-6.96 (m, 1H), 6.90 (brs, 1H), 3.88 (s, 3H), 3.60-3.48 (m, 4H), 2.89-2.78 (m, 4H), 1.52 (s, 9H). MS=554 (MH)+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][C:27]([O:29]CC)=[O:28])=[CH:20][CH:19]=1.O.Cl>O1CCCC1>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23][N:24]=[C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CON=C(CC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
Lithium hydroxide monohydrate (402 mg) was added to a solution of ethyl E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (1.16 g) in tetrahydrofuran (60 ml)-water (40 ml) and stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized to obtain 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (1.08 g, yield 99%) as colorless crystals. m.p. 107-108° C.