Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[C:4]#[C:5][CH3:6]>CC(C)=O>[I-:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CC#CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and 3-(4-(2-butynyloxy)-1,2,5-thiadiazol-3-yl)pyridine (578 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.88 g (95%).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:27])[NH:18][CH:19]4[CH:24]5[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]5)[CH2:20]4)[C:11]=3[N:12]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:43]>>[ClH:43].[ClH:43].[N:21]12[CH2:20][CH:19]([NH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:10]4[O:9][C:8]([N:7]5[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]5[CH3:1])=[N:12][C:11]=34)=[O:27])[CH:24]([CH2:23][CH2:22]1)[CH2:25][CH2:26]2
Reactant: ClCCl
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nc2c(C(=O)NC3CN4CCC3CC4)cccc2o1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1c1nc2c(C(=O)NC3CN4CCC3CC4)cccc2o1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice-cold solution of tert-butyl 3-methyl-4-(4-(quinuclidine-8-ylcarbamoyl)benzoxazole-2-yl)piperazine-1-carboxylate. (90 mg, 0.19 mmol) in CH2Cl2 (5 mL) was added TFA(0.25 mL, 3.2 mmol). The reaction mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The resulting TFA salt was converted to (S—N-(quinuclidine-8-yl)-2-(2-methylpiperazin-1-yl)benzoxazole-4-carboxamide dihydrochloride following GP-D1. 1H NMR and MS consistent.
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[C:42]=1B(O)O.CCCCCCC.C[CH2:60][O:61][C:62]([CH3:64])=[O:63]>>[CH3:60][O:61][C:62](=[O:63])[CH2:64][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:42]1[C:43]([O:47][CH3:48])=[CH:44][CH:45]=[CH:46][C:41]=1[F:40]
Reactant: CCOC(C)=O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cccc(F)c1B(O)O
Solvent: CCCCCCC
Product: COC(=O)CNc1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-pyridin-3-ylamino)-acetic acid methyl ester (example 176, intermediate b) and 2-fluoro-6-methoxyphenylboronic acid (CAS RN 78495-63-3) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (34%). MS (GC_MS (TIC): m/z=290.1 [M+.].
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH3:30])[C:26](=[O:31])[CH:25]=2)=[CH:18][N:17]=1)([O-])=O>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH3:30])[C:26](=[O:31])[CH:25]=2)=[CH:18][N:17]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccn(C)c(=O)c2)c(=O)[nH]1
Yield: 55.5 %

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.08 g) were refluxed in ethanol (10 ml) for 24 hours. The reaction mixture was cooled and evaporated under reduced pressure to afford a glassy residue which was washed with hot water yielding a white solid. This solid was filtered off, washed with water and recrystallised from methanol to yield 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.61 g); recrystallisation from aqueous methanol afforded the title compound, m.p. 202.5°-203.5° C.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[CH2:11](Br)[CH:12]=[CH2:13].[I-].[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>CCOCC>[C:19]([N:17]1[CH2:18][CH2:13][CH:12]([CH2:11][CH2:12][CH:13]=[C:16]([N:17]2[CH2:18][CH2:19][NH:17][C:19]2=[O:20])[CH3:18])[CH2:11][CH2:16]1)([O:20][C:12]([CH3:13])([CH3:16])[CH3:11])=[O:20]
Reactant: C=CCBr
Reactant: CN(C)C=O
Agent: [I-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: CCOCC
Product: CC(=CCCC1CCN(C(=O)OC(C)(C)C)CC1)N1CCNC1=O
Reaction time: 20 h
Yield: 15 %

Procedure:
To a stirred solution of 13 (1.5 g, 17 mmol) in DMF (75 mL) at ambient temperature was added LiN(TMS)2 (1M in hexanes, 17 mL) to effect a precipitate. Allyl bromide (1.6 mL, 19 mmol) was then added to the reaction mixture. After 15 min the homogeneous mixture was treated again with LiN(TMS)2 (14 mL) followed by the iodide 10 (5.9 g, 17 mmol) after 5 min. The reaction was stirred for 20 hr then diluted with ether. The ether portion was washed with water (2×), 5% KHSO4 and brine, dried (Mg SO4), and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave 14 (0.8 g, 15%) as a colorless oil. TLC Rf=0.46 (70% ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 5.80 (m, 1H), 5.23 (m, 2H), 4.10 (m, 2H), 3.82 (m, 2H), 3.30 (m, 6H), 2.72 (m, 2H), 1.70 (m, 3H), 1.50 (m, 2H), 1.46 (s, 9H), 1.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH2:27])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (1.5 g, 0.005 mol) was dissolved in dry N,N-dimethylformamide under argon and cooled to 0° C. 1,1′-Carbonyl-diimidazole (1.4 g, 0.009 mol) was added to the mixture and the reaction stirred for one hour while the temperature rose from 0° C. to room temperature. Ammonium acetate (5.6 g, 0.073 mol) was added and the reaction was stirred for one hour at room temperature. Water was added dropwise to the mixture and a precipitate appeared. The solid was filtrated, washed with water and dried under vacuum to yield 1.36 g (0.0041 mol, 91% of theory) of the title compound as a white solid. MS (m/e)=329.3(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:12][C:13]1[CH:44]=[CH:43][CH:42]=[CH:41][C:14]=1[CH2:15][NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:40])[C@@H:27]([OH:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:18]>CCOC(C)=O>[CH3:12][C:13]1[CH:44]=[CH:43][CH:42]=[CH:41][C:14]=1[CH2:15][NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:40])[C@@H:27]([OH:39])[C@@H:28]([NH:38][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=1[Cl:11])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[O:18]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reactant: Nc1cccc(C(=O)O)c1Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](NC(=O)c2cccc(N)c2Cl)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reaction time: 1 h
Yield: 81.9 %

Procedure:
DPP-Cl(68 μl) and TEA(50 μl) were added to a solution of 3-amino-2-chlorobenzoic acid (56 mg) in EtOAc (2 ml), and the mixture was stirred for one hour. After the addition of the compound obtained in Step 2 of Example 1 (141 mg) and TEA (50 μl), the mixture was stirred overnight. The reaction mixture was washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl, dried over MgSO4. After filtration and concentration, the residue was purified by silica gel column chromatography (CH2Cl2—MeOH), and reprecipitated from a mixture of CH2Cl2 and n-hexane to obtain the title compound (153 mg, 81%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[C:20](Cl)(=[O:22])[CH3:21].CN(C=O)C.CC(C)([O-])C.[K+]>O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:20](=[O:22])[CH3:21])[C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Reactant: CC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.1 g of 3-acetoxy-4-chloro-10H-phenothiazine (see Example 4) was added acetyl chloride (7 ml), DMF (5 ml) and potassium tert-butoxide (0.42 g). The reaction mixture was stirred at ambient temperature for 1 hour and then, poured in water. The resulting precipitate was filtred and purified by chromatography on silica gel to give (1.08 g) 3-acetoxy-10-acetyl-4-chloro-10H-phenothiazine (m.p. 155° C.).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:6]2)OCC1.[Br:15]Br.[NH2:17][C:18]([NH2:20])=[S:19]>Br>[BrH:15].[BrH:15].[CH2:12]([NH:11][CH:8]1[CH2:9][CH2:10][C:5]2[N:17]=[C:18]([NH2:20])[S:19][C:6]=2[CH2:7]1)[CH2:13][CH3:14]
Reactant: CCCNC1CCC2(CC1)OCCO2
Reactant: NC(N)=S
Reactant: BrBr
Agent: Br
Product: CCCNC1CCc2nc(N)sc2C1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
A solution of 12.0 g (60 mmol) (1,4-dioxa-spiro[4.5]dec-8-yl)-propyl-amine in 120 mL concentrated aqueous hydrobromic acid is stirred for 15 minutes at room temperature and then 3.12 mL (60 mmol) bromine are added. After further stirring for 15 minutes, 4.56 g (60 mmol) of thiourea is added. The resulting solution is stirred for another at room temperature until a white precipitation can be observed. Afterwards the mixture is heated for 2 hours at 90° C. The clear reaction mixture is then concentrated under vacuum. The solid residue is suspended in ethanol, heated to reflux and filtrated after cooling to room temperature. The resulting residue is dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][N:16]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1c(Cl)ccc2c(N3CCNCC3)ccnc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(Cl)ccc2c(N3CCN(C(=O)Nc4ccc(F)cc4)CC3)ccnc12

Procedure:
7-Chloro-8-methyl-4-(piperazin-1-yl)quinoline (80 mg, 0.31 mmol), 4-fluorophenyl isocyanate (57 μL, 0.5 mmol), and DMAP (2 mg) in THF (10 mL) are reacted according to method C yielding the product as a yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.[CH:28]12[N:35]([S:36]([CH2:39][C:40]3[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43](Br)=[CH:42][CH:41]=3)(=[O:38])=[O:37])[CH:32]([CH2:33][CH2:34]1)[CH2:31][CH2:30][CH2:29]2>>[CH:28]12[N:35]([S:36]([CH2:39][C:40]3[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43]([C:23]4[CH:27]=[CH:26][O:25][CH:24]=4)=[CH:42][CH:41]=3)(=[O:38])=[O:37])[CH:32]([CH2:33][CH2:34]1)[CH2:31][CH2:30][CH2:29]2
Reactant: COC(=O)c1c(CS(=O)(=O)N2C3CCCC2CC3)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)N2C3CCCC2CC3)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(8-azabicyclo[3.2.1]octane-8-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 186) as a white solid.
Reaction SMILES: CCN(CC)CC.[N:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N+:9]=[N-:10].C(Cl)(=O)C(C)(C)C.[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[N:8]([CH2:11][CH2:12][CH2:13][C:14]([N:32]1[C@@H:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:35][O:34][C:33]1=[O:36])=[O:16])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=NCCCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
NEt3 was added to a stirred mixture of 4-azidobutanoic acid in THF (0.3 M) cooled to −78° C. and stirring was continued at this temperature for 10 min. Pivaloyl chloride (1.3 eq) was added dropwise. The resulting mixture was warmed to 0° C. and stirred for 1 h before re-cooling to −78° C. In a separate flask, (4S)-4-benzyl-1,3-oxazolidin-2-one was dissolved in THF (0.8 M) and cooled to −78° C. before dropwise addition of N-BuLi (1.6M, 1.35 eq.) over 10 min. The mixture was stirred at −78° C. for 1 h and then transferred into the −78° C. solution of mixed anhydride using a syringe. The reaction was stirred at −78° C. for 1 h, then at RT for a further 1 h. The reaction was quenched by addition of sat. aq. NH4Cl before partitioning between H2O and EtOAc. The layers were separated and the aqueous phase re-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FC eluting with 10 to 30% EtOAc/PE to give the product as a colourless oil (74%). (ES+) m/z 289 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])C.[CH3:18][NH2:19].[F:20][C:21]([F:35])([F:34])[C:22]1[N:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1>>[CH3:18][NH:19][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:28]2[CH:29]=[CH:30][C:25]3[N:26]([C:22]([C:21]([F:35])([F:34])[F:20])=[N:23][N:24]=3)[CH:27]=2)[CH:8]=[CH:7][C:6]=1[O:12][C:13]([F:14])([F:15])[F:16]
Reactant: CCOC(=O)c1cc(Br)ccc1OC(F)(F)F
Reactant: CN
Reactant: OB(O)c1ccc2nnc(C(F)(F)F)n2c1
Product: CNC(=O)c1cc(-c2ccc3nnc(C(F)(F)F)n3c2)ccc1OC(F)(F)F

Procedure:
In a heavy-wall pressure tube was added ethyl-5-bromo-2-(trifluoromethoxy)benzoate (0.3 mL) and methylamine (1.5 mL). The mixture was heated at 60 C for 2 hours. The reaction mixture was concentrated to afford A which was coupled to with 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-ylboronic acid using methods disclosed above to give to give N-methyl-2-(trifluoromethoxy)-5-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzamide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1.[S:19]([O:24]C)([O:22][CH3:23])(=[O:21])=[O:20]>C1(C)C(C)=CC=CC=1>[CH3:23][O:22][S:19]([O-:24])(=[O:21])=[O:20].[CH3:1][N+:2]1[N:3]([CH3:23])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1C
Product: COS(=O)(=O)[O-]
Product: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Yield: 88 %

Procedure:
375 Grams (1.6 moles) of 1-methyl-3,5-diphenylpyrazole is dissolved in 1850 ml. of dry xylene and heated to 60° C. 208.13 Grams (1.65 moles) of dimethyl sulfate in 150 ml. of dry xylene is then added and the temperature of the reaction mixture raised to 105° C. to 110° C. and maintained there for 7.5 hours. The mixture is allowed to cool and then filtered. A brown solid is recovered, washed with xylene and then dry acetone to give the product in 88% yield, having a melting point of 155° C. to 157° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][C:30]3[CH:31]=[CH:32][C:26]4[O:25][C:24]([N:23]([CH3:22])[CH:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[N:28][C:27]=4[CH:29]=3)=[O:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4ccc(C5CCCCC5)cc4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Add oxalyl chloride (0.16 mL, 1.82 mmol) and 3 drops of DMF to a stirring suspension of 4-cyclohexyl-benzoic acid (0.197 g, 0.910 mmol) in CH2Cl2 (2.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4-cyclohexyl-benzoyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.05 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aqueous) (2×20 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.169 g, 62%). mass spectrum (m/e): 447.3 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.47 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.31-7.27 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 4.19-4.10 (m, 1H), 3.06 (s, 3H), 2.96 (d, J=12.0 Hz, 2H), 2.66-2.50 (m, 1H), 2.31 (s, 3H), 2.15 (dt, J=11.6, 2.4 Hz, 2H), 1.98-1.71 (m, 10H), 1.48-1.33 (m, 3H), 1.31-1.19 (m, 1H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:8]1[CH:23]=[CH:22][C:11]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([OH:21])=[CH:19][CH:20]=3)[NH:14][C:10]=2[CH:9]=1)([CH3:7])[CH3:6])=[O:2].O.[OH-].[K+].[CH3:27]I>C(O)C>[CH:1]([NH:3][CH2:4][C:5]([C:8]1[CH:23]=[CH:22][C:11]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:27])=[CH:19][CH:20]=3)[NH:14][C:10]=2[CH:9]=1)([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(CNC=O)c1ccc2nc(-c3ccc(O)nc3)[nH]c2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3ccc(C(C)(C)CNC=O)cc3[nH]2)cn1
Reaction time: 24 h

Procedure:
To a solution of 3.5 g. of the 5-(2-formylaminomethylprop-2-yl)-2-(6-hydroxypyridin-3-yl)-benzimidazole (prepared in Example 4d) in 20 ml. water and 13.6 ml. 1N potassium hydroxide solution in ethanol is added 0.85 ml. methyl iodide, while cooling with water. After 24 hours, it is filtered off with suction and purified by column chromatography (silica gel, elution agent dichloromethane:methanolic ammonia=20:1 v/v). Appropriate fractions are combined, the solvent is removed in a vacuum and the residue is digested with ethanol/water. After filtering off with suction, there are obtained 2.2 g. (57% of theory) of the title compound which, per mole, still contains 0.75 mole of water, as colourless crystals which, in the air, become reddish coloured; m.p. 217°-221° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[CH:14]=[N:13]1>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]([NH:21][C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][N:13]=[CH:14]3)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CC#N
Product: Brc1cn2ccnc2c(Nc2ccc3[nH]ncc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 1.00 equivalent (eq.) of 6,8-dibromo-imidazo[1,2-a]pyrazine and 1.00 eq. of 1H-Indazol-5-ylamine are dissolved in acetonitrile and placed into a sealed tube and heated at 100° C. for 24 hours. The mixture is cooled to room temperature (RT) and partitioned between ethyl acetate (EtOAc) and saturated (sat.) NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:12][C:13]=2[C:14]([O:16]CC)=O)=[CH:5][CH:4]=1.[NH3:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:12][C:13]=2[C:14]([NH2:25])=[O:16])=[CH:5][CH:4]=1
Reactant: N
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)nc1-c1ccc(OC)cc1
Product: COc1ccc(-c2nc(-c3ccccc3)[nH]c2C(N)=O)cc1
Temperature: 150 °C
Yield: 16 %

Procedure:
A suspension of ethyl 4-(4-methoxyphenyl)-2-phenyl-1H-imidazole-5-carboxylate (0.078 g, 0.23 mmol) in aqueous (28%) ammonia (4.5 ml) was heated in the microwave for 35 minutes at 150° C. The solvent was then removed in vacuo and the residue was purified by preparative HPLC to afford 4-(4-methoxyphenyl)-2-phenyl-1H-imidazole-5-carboxamide (0.0109 g, 0.04 mmol, 16%) as a white solid. 1H NMR (DMSO) δ 3.82 (3H, s), 7.01 (2H, d), 7.10 (1H, br. s), 7.39-7.43 (2H, m), 7.49 (2H, dd), 7.85 (2H, d), 8.10 (2H, m). LCMS (2) Rt: 2.46 min; m/z (ES+) 294.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7]F.[B:9]([F:12])([F:11])[F:10]>C(#N)C>[F:10][B-:9]([F:7])([F:12])[F:11].[F:10][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FB(F)F
Reactant: c1ccncc1
Reactant: FF
Solvent: CC#N
Product: F[B-](F)(F)F
Product: F[n+]1ccccc1
Reaction time: 5 h
Yield: 69 %

Procedure:
To a 30 ml anhydrous acetonitrile solution containing 0.71 g (8.98 mmole) of pyridine a mixed gas of fluorine and nitrogen (1:9) was introduced at a rate of 20 ml/min. at -40° C. under vigorous stirring, the amount of fluorine gas introduced being 26 mmoles. Subsequently, at the same temperature, 1 ml (8.13 mmole) of an ethereal complex of boron trifluoride as the Lewis acid was added and the resulting solution was stirred for 5 hours. The post treatment was effected as in example 13 to give 0.91 g (yield: 69%) of N-fluoropyridinium tetrafluoroborate, the physical properties of which are reproduced in Table 6.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)=[N:12][N:11]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].CO.O1CCCC1.[OH-].[Na+]>O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[N:12][N:11]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCc3ccc(C(=O)OCC)cc3)s2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(CSc2nnc(SCc3ccc(C(=O)O)cc3)s2)ccc(C(C)=O)c1O
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A mixture of 380 mg of ethyl p-[(5-[(4-acetyl-3-hydroxy-2-propylbenzyl )thio]-1,3,4-thiadiazol -2-yl)thiomethyl]benzoate, 2 ml of methanol, 2 ml of tetrahydrofuran and 2 ml of a 1N aqueous sodium hydroxide solution was stirred at 60° to 70° C. for 1 hour. After cooling, 20 ml cf water was added to the reaction mixture. The system was washed with ethyl acetate, made acidic with dil. hydrochloric acid and then, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol-water to give 100 mg of p-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thiomethyl]benzoic acid. The physical property of the thus obtained compound was identical with that of the compound obtained in Example 37.