Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:12][CH2:11]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.N1C=CC=CC=1>O1CCOCC1.OS([O-])(=O)=O.[K+].CCOCC>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:33])[N:9]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]#[C:17][CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:15]2)[CH3:8])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: CN(C(=O)Nc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reaction time: 0.75 h

Procedure:
A solution of 1.38 g (corresponds to 3.0 mmol) of trans-Methanesulfonic acid 3-(4-methylamino-cyclohexyl)-prop-2-ynyl ester trifluoroacetate in 7 ml dioxane was first cooled to 8° C., treated with 0.69 g (4.5 mmol) 4-chlorophenyl isocyanate and then with 1.2 ml (15 mmol; 5 equivalents) of pyridine (during 3 min). After 45 min at RT, the mixture was dissolved in aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.22 g (quantitative) of crude trans-Methanesulfonic acid 3-{4-[3-(4-chloro-phenyl)-1-methyl-ureido]-cyclohexyl}-prop-2-ynyl ester, MS: 398 (MH+, 1Cl). The crude product was directly used in the next step.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[C:6]1[SH:17])[CH3:4].S(OC)(O[CH3:22])(=O)=O>CO>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[C:6]1[S:17][CH3:22])[CH3:4]
Reactant: COS(=O)(=O)OC
Reactant: CCn1cc(-c2ccc(O)cc2)nc1S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(-c2ccc(O)cc2)nc1SC
Yield: 60 %

Procedure:
To a stirred solution of 3.25 parts of potassium hydroxide solution 86% in 80 parts of methanol are added 11 parts of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol and stirring is continued till all solid enters solution. Then there are added 6.9 parts of dimethyl sulfate and the whole is stirred overnight at room temperature. The precipitate is filtered off and the filtrate is evaporated. The solid residue is stirred with water. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 7 parts (60%) of 4-[1-ethyl-2-(methylthio)-1H-imidazol-4-yl]phenol; mp. 218.2° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](N)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].C1C=C2C3=C(C(NC(=O)C3=CC=C2)=O)C=1.N>C(OCCCC)(=O)C>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NC(=O)c2cccc3cccc1c23
Solvent: CCCCOC(C)=O
Product: C[Si](C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
4.5 ml of hexamethyldisilazane (22 mmoles) were added to a refluxing mixture of 5.0 g (30.1 mmoles) of 4-nitrobenzamide, 100 mg (0.5 mmole) of 1.8-naphthalimide and 20 ml of butyl acetate and the calculated amount of ammonia was evolved after refluxing for 35 minutes. The same experiment without catalyst was carried out and only 16% of the theoretical amount of ammonia was evolved after refluxing for 15 minutes. After refluxing for 1 hour, 83% of that amount of evolved.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14]I.O>CN(C)C=O>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CI
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 90.6 %

Procedure:
To solution of 4-bromo-2-nitro-benzoic acid (9 g, 36.58 mmol) in dimethylformamide (36 mL) cooled to 0° C. were added 1,8-diazabicyclo[5.4.0]und-7-ene (28.09 mL, 182.9 mmol) and MeI (11.4 mL, 182.5 mmol). The reaction mixture was stirred at 0° C. for 15 min and at r.t. for 48 h. The mixture was poured into water and extracted with EtOAc (2×). The combined organic phases were washed with water (2×), dried (Na2SO4) and concentrated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to give 4-bromo-2-nitro-benzoic acid methyl ester (8.62 g, 33.147 mmol, 90%). 1H-NMR (CDCl3, 400 MHz) 8.02 (s, 1H), 7.81 (dd, J=2.3, 10.5 Hz 1H), 7.66 (d, J=8.2 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7]1>S(=O)(=O)(O)O>[CH3:5][C:6]1([CH3:15])[CH2:10][C:9]2[CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=[CH:14][C:8]=2[O:7]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Cc2ccccc2O1
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2cc([N+](=O)[O-])ccc2O1
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
During a one hour period an ice cold mixture of 43 mL concentrated nitric acid and 50 mL of concentrated sulfuric acid was added dropwise to 100.0 g (0.67 mole) 2,3-dihydro-2,2-dimethylbenzofuran while maintaining the temperature of 5° C. After complete addition the mixture was stirred at 0° C. for 2.5 hours. The reaction mixture was poured into ice water and the total extracted with diethyl ether. The extract was dried over anhydrous magnesium chloride and filtered. Evaporation of the filtrate under reduced pressure produced a black oil. Purification of this oil by column chromatography on silica gel eluting with toluenen-hexane (9:1), yielded 50.0 g of 2,3-dihydro-2,2-dimethyl-5-nitrobenzofuran as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[F:32][C:13]1[C:12]2[O:11][C:10]3[C:19](=[CH:20][C:7]([C:41]4[C:36]([F:35])=[N:37][CH:38]=[CH:39][CH:40]=4)=[CH:8][CH:9]=3)[C@@:18]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:17]=2[CH:16]=[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:14]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(N3CCOCC3)cc12
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(N3CCOCC3)cc12
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A resealable vial was charged with (S)-2-amino-4′-fluoro-2′-morpholino-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (125 mg, 0.248 mmol; prepared by steps analogous to those described in Method BB40 and Example 2), tetrakis(triphenylphosphine)palladium(0) (28.7 mg, 0.025 mmol), 2-fluoropyridin-3-ylboronic acid (56.0 mg, 0.397 mmol), DMF (1.2 mL) and 2 M aqueous sodium carbonate (372 μL, 0.745 mmol). The vial was sealed and the mixture was stirred for 2 hr at 85° C. The mixture was cooled and diluted with ethyl acetate (6 mL) and water (2 ml). The organic layer was loaded onto 2 g SCX column and washed with EtOAc and MeOH/DCM 1:1. The material was recovered from the column with 2 M ammonia in MeOH, concentrated and purified by silica gel chromatography using 15-60% DCM/MeOH/NH4OH 90:10:1 in DCM to give a solid that was sonicated with 2 mL of DCM, then filtered and dried to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholino-5H-spiro[oxazole-4,9′-xanthen]-2-amine MS m/z=451.0 [M+H]+. Chemical Formula: C24H20F2N4O3. Exact Mass: 450.15.
Reaction SMILES: CN(CC[C:6]1[C:10]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])([CH:11]([CH2:13][CH2:14][CH3:15])[CH3:12])[CH:9]=[CH:8][CH:7]=1)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:32]([N:36]([CH:41](O)[CH3:42])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([N:36]([CH2:41][CH2:42][C:9]1[C:10]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])([CH:11]([CH2:13][CH2:14][CH3:15])[CH3:12])[CH:6]=[CH:7][CH:8]=1)[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(C)C1(C(C)CCC)C=CC=C1CCN(C)C
Reactant: CCCCN(CCCC)C(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCCCN(CCCC)CCC1=CC=CC1(C(C)CCC)C(C)CCC

Procedure:
The reaction is carried out in a manner identical to that for (dimethylaminoethyl)-di-(2-pentyl)cyclopentadiene, the tosylate of N,N-di-n-butylaminoethanol being prepared in situ. The conversion was 88%. The (di-n-butylaminoethyl)-di-(2-pentyl)cyclopentadiene was obtained after preparative column purification on silica gel using, successively, petroleum ether (40-60° C.) and THF, followed by distillation under reduced pressure, the yield being 51%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]2[N:32]=[C:33]([NH2:35])[S:34][C:30]=2[CH:29]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:35][C:33]3[S:34][C:30]4[CH:29]=[C:28]([F:27])[CH:37]=[CH:36][C:31]=4[N:32]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1nc2ccc(F)cc2s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nc2ccc(F)cc2s1
Yield: 37.4 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 6-fluorobenzo[d]thiazol-2-amine (0.067 g, 0.397 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of desired product. 1HNMR (DMSO-d6): δ 3.99 (s, 3H), 7.32 (t, J=7.2 Hz, 1H), 7.51 (t, J=9.3 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.68-7.80 (m, 4H), 7.94 (t, J=6.3 Hz, 2H), 11.98 (s, 1H), 12.83 (br s, 1H); MS (m/z): 512.97 [M−H]−.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCC(NS(C)(=O)=O)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask was placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of methanesulfonyl chloride (29.1 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:13]=1)[C:11]#[N:12].O.[NH2:20][NH2:21]>C(O)CCC.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:5][C:6]1[CH:13]=[C:10]2[C:9](=[CH:8][CH:7]=1)[NH:21][N:20]=[C:11]2[NH2:12]
Reactant: NN
Reactant: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Temperature: 120 °C
Yield: 62 %

Procedure:
A mixture of 5-(3,5-difluoro-benzyl)-2-fluoro-benzonitrile (20 g, 80.9 mmol) and hydrazine hydrate (19.6 mL, 404 mmol) in n-butanol (200 mL) was heated at 120° C. overnight. The reaction mixture was diluted with water/ethyl acetate and the organic phase washed twice with brine, dried and evaporated. Crude was triturated with diethyl ether and filtered to afford 13 gr of final product. Purification of the resulting organic phase by chromatography over silica gel (DCM/EtOH 95:5) afforded further 6.3 g of the title compound (total amount 19.2 g, 92% yield).
Reaction SMILES: O.O.Cl[Sn]Cl.Cl.[N+:7]([C:10]1[CH:11]=[C:12]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[CH:13]=[CH:14][C:15]=1[NH2:16])([O-])=O>>[NH2:7][C:10]1[CH:11]=[C:12]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([NH2:24])[CH:18]=2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Nc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Yield: 70 %

Procedure:
A 50 ml single neck round bottomed flask equipped with condenser, and stirring magnetic bar were placed SnCl2.2H2O (6 g, 26.5 mmol) and 12.5 ml concentrated hydrochloric acid and reaction mixture was stirred and than 3,3′-dinitrobenzidine formula 2 where in R═CH3 (DNB) (1.176 g, 4 mmol) was added in small portions over 15 minute to maintain the reaction temperature less than 60° C. The thick slurry was then stirred for additional 2 hours at 40° C. to complete the reduction. The salt of the tetramine was precipitated out, which was neutralized with cold 10% NaOH solution and the solid filtered out, washed with water dried under vacuum to give 3,3′-diaminobenzidine (DAB) in 70% yield (0.655 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].CO[C:10]([NH:12][C@H:13]([C:23]1[NH2+:24][C:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:26][N:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])=[O:11].O[Li].[OH2:40]>C1COCC1.O>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:3]([C:10]([NH:12][C@H:13]([C:23]1[NH2+:24][C:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:26][N:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])=[O:11])([OH:4])=[O:40]
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC)C1=NC=C(c2ccc3ccccc3c2)[NH2+]1
Reactant: O
Agent: O=C([O-])C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Product: CCC(=O)CCCCC[C@H](NC(=O)C(=O)O)C1=NC=C(c2ccc3ccccc3c2)[NH2+]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl ({(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxononyl}amino)(oxo)acetate (Prepared as in example 147) was dissolved in THF and a solution of LiOH.H2O (1.05 eq.) in H2O was added and the mixture was then stirred for 1 hr at RT. The reaction was quenched with 1M HCl until pH 5 was reached and then the THF was removed under reduced pressure. The aqueous phase was extracted with DCM (3×); the combined organic phases were washed with brine and then dried (Na2SO4) and concentrated under reduced pressure. The resulting crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound as colorless oil. 1H NMR (300 MHz, DMSO-d6) δ: 9.39 (1H, d, J=8.2 Hz), 8.30 (1H, s), 8.11-7.85 (6H, m), 7.58-7.47 (2H, m), 6.88-6.18 (1H, bs), 5.15-5.02 (1H, m), 2.45-2.36 (4H, m), 2.13-1.87 (2H, m), 1.55-1.41 (2H, m), 1.40-1.20 (4H, m), 0.90 (3H, t, J=7.3 Hz). MS (ES) C24H27N3O4 requires: 421, found: 422 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[Br:26]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([Br:26])=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(Br)c12

Procedure:
Put 1.75 g (5.15 mmol) 6-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]hexanoic acid methyl ester in 5.2 ml tetrachloromethane. At RT, add 1.054 g (5.92 mmol) N-bromosuccinimide and then heat the mixture under reflux for approx. 1 h. After cooling, concentrate by vacuum evaporation and chromatograph the residue on silica gel (solvent: cyclohexane/ethyl acetate 4:1). 0.89 g (41.2% of theor.) of the target compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[CH3:16])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>C(O)(C)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][C:10]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Solvent: CC(C)O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(I)cc34)cc2C)cn1
Yield: 69.1 %

Procedure:
4-(6-methylpyridin-3-yloxy)-3-methylbenzenamine (812 mg, 3.79 mmol) and 4-chloro-6-iodo-quinazoline (1 g, 3.4 mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 1.1 g of the clean desired material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][C:3]=1[O:25]C.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][C:3]=1[OH:25]
Reactant: COc1cc(-n2c(C[C@@H]3CCN(C(=O)C4CC4)C3)n[nH]c2=O)ccc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)c(O)c2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a round bottom flask, 4-[4-bromo-3-(methyloxy)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.349 mmol) was dissolved in dichloromethane (3.5 mL) and cooled to 0° C. Boron tribromide (2.443 mmol) was added to the solution slowly, which was then allowed to warm to room temperature. The reaction was stirred for 1 h, and analysis by LCMS indicated complete conversion to desired product. The reaction was poured into a reparatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the title product as a tan solid (110 mg, 77%). MS(ES)+ m/e 407.1, 408.9 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)Cc1cccc(OCCCCl)c1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(CCCOc2cccc(CC(=O)O)c2)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(3-chloro-propoxy)-phenylacetic acid (0.5 g, 2.2 mmol) and N-methylpiperazine (1.9 mL) was heated at 60° C. overnight. The reaction was diluted with water and purified by preparative HPLC to give the product as a clear gel. (0.6 g, 94%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[Na+]>CN(C=O)C.CCOC(C)=O>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CC#N)c1

Procedure:
Methyl 3-(bromomethyl)benzoate (8.5 g, 37 mmol) and sodium cyanide (1,8 g, 37 mmol) were stirred at room temperature in DMF (40 mL) overnight. The mixture was diluted with EtOAc and extracted several times with water containing a small amount of brine, then brine, dried (MgSO4), and solvent removed in vacuo. The crude product (6.8 g, yellow oil) was sufficiently pure to be used in the next step without purification. IR(neat): cm-1 2249, 1722. 1H-NMR(300 MHz, CDCl3): 8.03-8.01 (m, 2H), 7.57-7.46 (m, 2H), 3.94 (s, 3H), 3.82 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[S:26][CH:27]=1
Reactant: OCc1cc(Cl)cs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Cl)cs4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 4-chlorothiophen-2-methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated in vacuo, and diluted with DCM. The organic layer was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography, (MeOH/DCM) to afford the title compound (53 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([F:19])=[C:13]([F:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1.C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[CH:14][C:13]([F:18])=[C:12]([F:19])[CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc(F)c(F)cc3c2=O)cc1C
Reactant: BrCc1cccc(Br)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cc(F)c(F)cc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 74 mg (0.24 mmol) of 3-(3,4-dimethyl-benzoyl)-6,7-difluoro-1H-quinolin-4-one, 71 mg (0.28 mmol) of 2-bromo-6-bromomethyl-pyridine, 0.57 mL of 0.5M toluene solution of potassium bis(trimethylsilyl)amide and 2 mL of THF. Yield: 73 mg of a white solid: LC-MSD, m/z for C24H17BrF2N2O2 [M+H]+=483.4, 485.4; HPLC retention time: 2.6 min.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C.C(OCC)C>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=1
Reactant: Ic1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ml) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-iodo-1-trityl-]H-imidazole (104.1, 93%) as a white solid. MH+(437)