Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[CH2:29]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:29])[CH:15]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cccs4)C3)cc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4cccs4)C3)cc21

Procedure:
A mixture of 200 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piperazinyl]-3-quinolinecarboxylic acid, 0.3 ml of 37% formalin and 0.35 ml of 90% formic acid was refluxed for 2 hours, then evaporated. A 10 ml portion of water was added and the mixture neutralized with 1N sodium hydroxide. The solid was collected, washed with water, methanol, ether and dried, giving 170 mg of the desired product, mp 238°-240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:12]=1.I.CS[C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[NH:30]>C(O)C>[CH3:25][N:17]([CH:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[NH:30])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CSC(=N)c1cccs1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Agent: I
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 73.3 %

Procedure:
A solution of compound 82 (0.44 g, 1.281 mmol) in dry ethanol (20 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.73 g, 2.562 mmol) at room temperature and stirred for 24 h. The solvent was evaporated and product was precipitated with ether (100 mL). The solid was dissolved into sat. NaHCO3 sol.: CH2Cl2 (50 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 83 (0.425 g, 73%) as a foam in 1:2 ration of diastereomers. 1H NMR (DMSO-d6) δ 1.38-1.56 (m, 11H), 1.64-1.82 (m, 4H), 2.06-2.18 (m, 2H), 2.62-2.70 (m, 4H), 3.80-3.90 (m, 1H), 6.27 (brs, 1H), 6.62-6.66 (m, 1H), 6.95-7.11 (m, 3H), 7.22-7.29 (m, 1H), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.6 Hz), 10.59, 10.63 (2s, 1H); ESI-MS m/z (%): 453 (MH+, 100).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[C:17]1(S)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][C:10]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(Sc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, thiophenol and DBU in dioxane. EI-MS m/e (%): 349 (M{81Br}+, 40), 348 ([M{81Br}-H]+, 28), 347 (M{79Br}+, 39), 346 ([M{79Br}-H]+, 24), 268 ([M—Br]+, 100), 175 (92).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:17]([O-])=O)[CH:4]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:17])[C:6](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:7]([OH:9])=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCCCCl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(C(=O)O)cc1OCCCCl
Temperature: 40 °C
Yield: 100.4 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 4.00 g (13.5 mmol) of 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoic acid (purity: 99%) obtained in Reference Example III-14, and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.4 g of 5 wt. % palladium/carbon (containing 49% water) at the same temperature. The resulting mixture was heated to the same temperature for 4 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 3.52 g (isolated yield: 98.1%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of 4-methoxy-5-(3-chloropropoxy)-anthranilic acid as a white crystalline product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1([CH3:28])[CH2:24][NH:23][CH:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C:20]([CH3:28])([CH3:19])[CH2:21][CH:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC1(C)CNC(C(N)=O)C1
Agent: Cl
Product: CC1(C)CC(C(N)=O)N(C(=O)c2ccc(C3CC3)c(OCC3CC3)n2)C1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 4,4-dimethyl-pyrrolidine-2-carboxylic acid amide hydrochloride (84.3 mg, 472 μmol) as starting materials and isolated (145 mg, 95%) as white foam; LC-MS (UV peak area, ESI) 100%, 358.2124 [MH+].
Reaction SMILES: O[C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:23])=O>CN(C)C=O>[Cl:23][C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cnn2c1c(O)nc1c(C)nn(C)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2c1c(Cl)nc1c(C)nn(C)c12

Procedure:
92.5 gms. of 5-hydroxy-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, together with 300 ml. of phosphorus oxychloride and 3 ml. of dimethylformamide are refluxed for 5 hours. After distilling off the phosphorus oxychloride, the reaction mixture is poured onto ice and the crude 5-chloro-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid ethyl ester, is filtered under suction, then recrystallized from acetone, yield 83 gms. of white crystals, m.p. 130°-132°.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[CH3:19].[S-:20][C:21]#[N:22].[NH4+].BrBr>C(O)(=O)C>[NH2:22][C:21]1[S:20][C:18]2[CH:17]=[C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=3)[CH:4]=[C:3]([CH3:19])[C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Oc2cc(C)c3nc(N)sc3c2)ccn1

Procedure:
To the solution of 4-(4-amino-3-methylphenoxy)-N-methylpicolinamide (25 mg, 0.097 mmol, 1.0 eq) in 1 mL of cold acetic acid was added ammonium thiocyanate (11 mg, 0.145 mmol, 1.5 eq). After stirring for a few minutes, bromine (6 μL, 0.116 mmol, 1.2 eq) was injected dropwise and reaction stirred at room temperature for 3 hours. Thereafter, reaction was quenched with NaHCO3 saturated solution (ca. 10 mL) and extracted with ethyl acetate (ca. 25 mL×3), combined organic extracts were dried over sodium sulfate and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification. LC/MS (m/z) [315.1] (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:28][CH2:29][C:30]([C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=3)([OH:33])[CH2:31][CH2:32]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1ccc(Cl)c(Cl)c1)CC2
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 35.3 %

Procedure:
1-Bromo-3,4-dichlorobenzene (1.35 g, 5.98 mmol) in THF (10 mL) was added drop-wise to a solution of n-BuLi (1.6 M in hexanes, 4 mL) at −78° C. The mixture was stirred for 40 min at −78° C. A solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g, 3.74 mmol) in THF (10 mL) was added drop-wise and the mixture was stirred for 1 h at −78° C. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted twice with diethyl ether. The combined organic phase was washed with brine dried (sodium sulfate), filtered and evaporated to give 2.2 g of crude material. Precipitation in heptane and diethyl ether gave 547 mg of 9-(3,4-dichloro-phenyl)-9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-ESI-HRMS of [M+H]+ shows 296.0983 Da. Calc. 296.09728 Da, dev. 3.4 ppm.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[Cl:5][CH:6]1[C:12]2=[N:13][C:14]([CH3:22])=[C:15]([C:17](OCC)=[O:18])[CH:16]=[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7]1>CC(O)C>[Cl:5][CH:6]1[C:12]2=[N:13][C:14]([CH3:22])=[C:15]([C:17]([NH:3][C:2]([NH2:4])=[NH:1])=[O:18])[CH:16]=[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(Cl)CCCC2
Reactant: N=C(N)N
Solvent: CC(C)O
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.7 %

Procedure:
In an atmosphere of argon, guanidine hydrochloride (4.08 g, 42.7 mmol) was added to 28% sodium methoxide methanol solution (8.0 ml, 41.5 mmol) at 0° C. After 30 minutes of stirring at the same temperature, the thus precipitated sodium chloride was removed by filtration using a glass filter and the resulting filtrate was evaporated under reduced pressure to obtain free guanidine. Guanidine and ethyl 9-chloro-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.10 g, 4.12 mmol) were suspended in 2-propanol (6.0 ml) and stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was mixed with water and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1-5:1) to obtain the title compound (494.0 mg, 42.7%) as white powder.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[S:9][CH:8]=1
Reactant: BrBr
Reactant: O=c1[nH]cnc2ccsc12
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)csc12
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Thieno[3,2-d]pyrimidin-4(3H)-one (12.5 g) was dissolved in acetic acid (52 mL), and bromine (13 mL) was added thereto. The reaction mixture was stirred at 120° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature and distilled under reduced pressure to remove acetic acid. The reaction mixture was placed in ice water, and the solid thus obtained was filtered and washed with ether, and dried to obtain the title compound (7.8 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30](Cl)[C:31](OCC)=[O:32])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:38][C:39]([NH2:41])=[S:40].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:40][C:39](=[NH:38])[NH:41][C:31]3=[O:32])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCCC2(C)CCc3c(C)c(OC(C)=O)c(OC)c(OC)c3O2)cc1
Solvent: O=S1(=O)CCCC1
Product: COc1c(OC(C)=O)c(C)c2c(c1OC)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2

Procedure:
The procedure described in Example 1(a) was repeated, except that 558 mg of ethyl 3-{4-[2-(6-acetoxy-7,8-dimethoxy-2,5-dimethylchroman-2-yl)ethoxy]phenyl}-2-chloropropionate, 100 mg of thiourea and 12 ml of sulfolane were heated at 110°-115° C. for 3.5 hours. The product was subsequently treated as described in Example 1(a), except that the crude product, in the form of an oil, was purified by column chromatography through silica gel, eluted with a 20:1 by volume mixture of ethyl acetate and methanol, to give the title compound, softening at 103°-110° C.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:13].C(O)(=O)C.BrBr>C(O)(=O)C>[Br:13][CH2:2][C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1cnc2ccccn12
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cnc2ccccn12
Temperature: 40 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
22.1 g of 3-acetylimidazo[1,2-a]pyridine was dissolved in 220 ml of acetic acid. 35.1 ml of a 30% hydrogen bromide/acetic acid solution was added dropwise to the solution at 0° C. Then 28.6 g of bromine was added dropwise thereto at 40° C. The mixture was stirred at 40° C. for 2 h and crystals thus formed were filtered. The crystals were dissolved in 100 ml of water. The solution was made alkaline with an excess of an aqueous sodium hydrogencarbonate solution and then extracted with ethyl acetate. The organic layer was concentrated and the obtained brown solid was purified according to silica gel column chromatography (eluted with ethyl acetate) to obtain 13.5 g (yield: 40%) of 3-bromoacetylimidazo[1,2-a]pyridine (yield: 40%) in the form of yellow crystals. ii) A suspension comprising 1.91 g (6.0 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 3.0 g of potassium carbonate and 40 ml of dimethylformamide was stirred at 80° C. for 1 h. After cooling to room temperature, 1.99 g of 3-bromoacetylimidazo[1,2-a]pyridine prepared in the above step i) was added thereto and the mixture was stirred at room temperature for 6 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a solid residue, which was then purified according to silica gel column chromatography (chloroform:methanol =96.4). The purified product was converted into its dihydrochloride with ethanolic hydrogen chloride and recrystallized from methanol/acetone to obtain 1.75 g (yield: 58%) of the intended compound.
Reaction SMILES: CS(C)=O.[CH2:5]([C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12]([CH2:51]OS(C)(=O)=O)=[C:11]([Cl:57])[N:10]=1)[CH2:6][CH2:7][CH3:8].[N-:58]=[N+:59]=[N-:60].[Na+].[Na+].[Cl-]>CCOC(C)=O>[N:58]([CH2:51][C:12]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[N:10][C:11]=1[Cl:57])=[N+:59]=[N-:60]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc(Cl)c(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(Cl)c(CN=[N+]=[N-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of intermediate (11c) (15 g, 20 mmol) was added sodium azide (3.9 g, 60 mmol). The mixture was stirred at room temperature for 20 minutes. EtOAc (500 mL) and saturated aqueous NaCl (100 mL) were added and the layers were separated, retaining the organic layer. The organic was washed an additional three times with saturated aqueous NaCl (100 mL). After drying over sodium sulfate and filtration, the removal of solvent provided intermediate (11d) as a yellow solid (12 g), which was used directly in the next step. MS m/z: [M+H+] calcd for C41H36ClN9, 690.29. found 690.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>CO.O1CCOCC1>[ClH:21].[CH2:14]([CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(CC2CCCNC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(t-butoxycarbonyl)-3-benzylpiperidine (400 mg, 1.45 mmol) in methanol (5 mL) was added hydrogen chloride in dioxane (4M, 15 mL). The resulting yellow solution was stirred for 1 hr, at which time the reaction was concentrated in vacuo to provide 3-benzylpiperidine hydrochloride (308 mg, 100%) as an amorphous solid. 1H NMR (300 MHz, CD3OD), δ: 7.27 (m, 2H,), 7.19 (m, 3H), 3.29 (br. d, 1H, J=12 Hz), 3.20 (br. d, 1H, J=12 Hz), 2.87 (br. t, 1H, J=12 Hz), 2.67 (m, 1H), 2.60 (d, 2H, J=7 Hz), 2.08 (m, 1H) 1.70-1.87 (m, 3H), 1.26 (m, 1H). MS (CI), m+/z: (M+H)+=176.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([C:14]1[NH:15][CH:16]=[C:17]([CH3:19])[N:18]=1)[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:12]([C:14]1[N:15]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:16]=[C:17]([CH3:19])[N:18]=1)[CH3:13]
Reactant: CCc1nc(C)c[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1nc(C)cn1-c1cc(F)ccc1[N+](=O)[O-]

Procedure:
Combine 100 g of 2,4-difluoronitrobenzene, 69 g of 2-ethyl-4-methylimidazole and 100 g of K2CO3 in 700 mL of acetonitrile, and stir at room temperature for 4 days. Remove the solvent under vacuum. Slurry the residue in 300 mL of CH2Cl2 and chromatograph over 1 kg of silica gel using CH2Cl2. Combine the appropriate fractions and remove the solvent under vacuum. Crystallize the residue from pet ether to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:10])=[CH:5][CH:4]=1>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(C(=O)c1ccc(O)cc1)c1ccccc1
Yield: 63.1 %

Procedure:
A solution of 50 g (0.21 mole) of 4-methoxybenzil in 250 ml of acetic acid and 300 ml of 48% hydrobromic acid was heated to reflux for 10 hours. A solid that separated on cooling was recovered by filtration and the filtrate extracted with ether. The solid was dissolved in ether, the ether solutions combined and extracted with 10 % potassium hydroxide. The potassium hydroxide solution was washed with ether and neutralized with hydrochloric acid. The resulting solid was dissolved in ether, the solution dried over magnesium sulfate, and the ether removed by distillation. The resulting dark, brown solid was recrystallized from benzene to yield 30 g (64%) of 4-hydroxybenzil; mp, 138°-140°, lit., 129°-130°.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[NH2:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[NH:13][C:12](=[O:17])[C:11]=1[Cl:18]>CN(C)C=O>[ClH:18].[Cl:18][C:11]1[C:12](=[O:17])[NH:13][C:14](=[O:16])[NH:15][C:10]=1[CH2:9][NH:8][C:2](=[NH:7])[CH3:3]
Reactant: NCc1[nH]c(=O)[nH]c(=O)c1Cl
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=N)NCc1[nH]c(=O)[nH]c(=O)c1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 52.7 %

Procedure:
To a solution of 705 mg of ethyl acetoimidate hydrochloride in N,N-dimethylformamide (12 ml), 500 mg of 6-aminomethyl-5-chlorouracil were added, followed by stirring at room temperature for 13 hours. After the reaction mixture was allowed to cool down, a crystallized matter was collected by filtration and then washed with a 10% solution of hydrochloric acid in methanol, whereby 190 mg of the title compound were obtained (yield: 26%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:23][C:22]=4[CH:35]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:23][C:22]=4[CH:35]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)CCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)O)CCO4)no2)cc1C#N
Reaction time: 2 h
Yield: 9.2 %

Procedure:
Ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]propanoate (Preparation 78) (0.092 g, 0.193 mmol) was dissolved in Ethanol (2 ml). Then 2N NaOH (1 ml, 2.000 mmol) was added and the reaction mixture left standing at RT for 2 hours. Ethanol was removed by evaporation and the resulting residue dissolved in EtOAc and water, acidified with acetic acid and the layers separated. Solid separated from the aqueous phase and was filtered off solid and dried under vacuum overnight at 50° C. to give the title compound (8 mg) as a white solid. δH (d6DMSO, 400 MHz): 1.37 (6H, d), 2.38 (2H, t), 2.67 (2H, m), 3.03 (2H, m), 3.89 (2H, s), 4.07 (2H, m), 4.97 (1H, m), 7.14 (1H, d), 7.54 (1H, d), 7.89 (1H, dd), 7.98 (1H, d), 8.39 (1H, dd), 8.51 (1H, d); MS (ES): C24H24N4O5 requires 448; found 449 [M+H]+.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:43])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[N:21][CH:20]=3)[CH:14]=2)[C:8]1=[O:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.C(=O)([O-])O.[Na+].ClCCl>CO>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[NH:23][CH:22]=[N:21][CH:20]=3)[CH:14]=2)[CH3:43])[C:8]1=[O:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cnc[nH]2)c1
Temperature: 25 °C
Yield: 6.6 %

Procedure:
To a solution of 3-hexyl-6-methyl-6-[3-(1-triphenylmethyl-1H-imidazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 74, 55 mg, 0.95 mmol) in methanol (1.5 ml) was added aqueous hydrochloric acid (2M, 0.5 ml) and the mixture was heated under reflux for 16 h. The reaction mixture was then cooled to room temperature and poured onto solid sodium hydrogen carbonate. Dichloromethane was added, the layers were separated and the organic extracts were dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a clear oil (21 mg, 66%).